Therapeutic Combination of PI3K Inhibitor and a BTK Inhibitor

ABSTRACT

In some embodiments, the invention includes a therapeutic combination of a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms, and a Bruton&#39;s tyrosine kinase (BTK) inhibitor. In some embodiments, the invention includes therapeutic methods of using a BTK inhibitor and a PI3K-δ inhibitor to treat solid tumor cancers by modulation of the tumor microenvironment, including macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts.

FIELD OF THE INVENTION

A therapeutic combination of a phosphoinositide 3-kinase (PI3K)inhibitor and a Bruton's Tyrosine Kinase (BTK) inhibitor and uses of thetherapeutic combination are disclosed herein.

BACKGROUND OF THE INVENTION

PI3K kinases are members of a unique and conserved family ofintracellular lipid kinases that phosphorylate the 3′-OH group onphosphatidylinositols or phosphoinositides. PI3K kinases are keysignaling enzymes that relay signals from cell surface receptors todownstream effectors. The PI3K family comprises 15 kinases with distinctsubstrate specificities, expression patterns, and modes of regulation.The class I PI3K kinases (p110α, p110β, p110δ, and p110γ) are typicallyactivated by tyrosine kinases or G-protein coupled receptors to generatePIP3, which engages downstream effectors such as those in the Akt/PDK1pathway, mTOR, the Tec family kinases, and the Rho family GTPases.

The PI3K signaling pathway is known to be one of the most highly mutatedin human cancers. PI3K signaling is also a key factor in disease statesincluding hematologic malignancies, non-Hodgkin lymphoma (such asdiffuse large B-cell lymphoma), allergic contact dermatitis, rheumatoidarthritis, osteoarthritis, inflammatory bowel diseases, chronicobstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma,disorders related to diabetic complications, and inflammatorycomplications of the cardiovascular system such as acute coronarysyndrome. The role of PI3K in cancer has been discussed, for example, inJ. A. Engleman, Nat. Rev. Cancer 2009, 9, 550-562. The PI3K-δ and PI3K-γisoforms are preferentially expressed in normal and malignantleukocytes.

The delta (δ) isoform of class I PI3K (PI3K-δ) is involved in mammalianimmune system functions such as T-cell function, B-cell activation, mastcell activation, dendritic cell function, and neutrophil activity. Dueto its role in immune system function, PI3K-δ is also involved in anumber of diseases related to undesirable immune response such asallergic reactions, inflammatory diseases, inflammation mediatedangiogenesis, rheumatoid arthritis, auto-immune diseases such as lupus,asthma, emphysema and other respiratory diseases. The gamma (γ) isoformof class I PI3K (PI3K-γ) is also involved in immune system functions andplays a role in leukocyte signaling and has been implicated ininflammation, rheumatoid arthritis, and autoimmune diseases such aslupus.

Downstream mediators of the PI3K signal transduction pathway include Aktand mammalian target of rapamycin (mTOR). One important function of Aktis to augment the activity of mTOR, through phosphorylation of TSC2 andother mechanisms. mTOR is a serine-threonine kinase related to the lipidkinases of the PI3K family and has been implicated in a wide range ofbiological processes including cell growth, cell proliferation, cellmotility and survival. Disregulation of the mTOR pathway has beenreported in various types of cancer.

In view of the above, PI3K inhibitors are prime targets for drugdevelopment, as described in J. E. Kurt and I. Ray-Coquard, AnticancerRes. 2012, 32, 2463-70. Several PI3K inhibitors are known, includingthose that are PI3K-δ inhibitors, PI3K-γ inhibitors, and PI3K-δ,γinhibitors.

Bruton's Tyrosine Kinase (BTK) is a Tec family non-receptor proteinkinase expressed in B cells and myeloid cells. The function of BTK insignaling pathways activated by the engagement of the B cell receptor(BCR) and FCER1 on mast cells is well established. Functional mutationsin BTK in humans result in a primary immunodeficiency diseasecharacterized by a defect in B cell development with a block betweenpro- and pre-B cell stages. The result is an almost complete absence ofB lymphocytes, causing a pronounced reduction of serum immunoglobulin ofall classes. These findings support a key role for BTK in the regulationof the production of auto-antibodies in autoimmune diseases.

Other diseases with an important role for dysfunctional B cells are Bcell malignancies. The reported role for BTK in the regulation ofproliferation and apoptosis of B cells indicates the potential for BTKinhibitors in the treatment of B cell lymphomas. BTK inhibitors havethus been developed as potential therapies, as described in O. Cruz etal., OncoTargets and Therapy 2013, 6, 161-176.

In many solid tumors, the supportive microenvironment (which may make upthe majority of the tumor mass) is a dynamic force that enables tumorsurvival. The tumor microenvironment is generally defined as a complexmixture of “cells, soluble factors, signaling molecules, extracellularmatrices, and mechanical cues that promote neoplastic transformation,support tumor growth and invasion, protect the tumor from host immunity,foster therapeutic resistance, and provide niches for dominantmetastases to thrive,” as described in Swartz et al., Cancer Res., 2012,72, 2473. Although tumors express antigens that should be recognized byT cells, tumor clearance by the immune system is rare because of immunesuppression by the microenvironment. Addressing the tumor cellsthemselves with e.g. chemotherapy has also proven to be insufficient toovercome the protective effects of the microenvironment. New approachesare thus urgently needed for more effective treatment of solid tumorsthat take into account the role of the microenvironment.

The present invention provides the unexpected finding that thecombination of a PI3K inhibitor with a BTK inhibitor is effective in thetreatment of any of several types of cancers such as leukemia, lymphomaand solid tumor cancers.

SUMMARY OF THE INVENTION

In an embodiment, the invention provides a composition comprising a PI3Kinhibitor and a BTK inhibitor in combination. This composition istypically a pharmaceutical composition.

In an embodiment, the invention provides a composition comprising aPI3K-γ inhibitor and a BTK inhibitor in combination. This composition istypically a pharmaceutical composition.

In an embodiment, the invention provides a composition comprising aPI3K-δ inhibitor and a BTK inhibitor in combination. This composition istypically a pharmaceutical composition.

In an embodiment, the invention provides a composition comprising aPI3K-γ,δ inhibitor and a BTK inhibitor in combination. This compositionis typically a pharmaceutical composition.

In an embodiment, the invention provides a pharmaceutical compositioncomprising a PI3K inhibitor and a BTK inhibitor in combination for usein the treatment of leukemia, lymphoma or a solid tumor cancer.

In an embodiment, the invention provides a pharmaceutical compositioncomprising a PI3K-γ inhibitor and a BTK inhibitor in combination for usein the treatment of leukemia, lymphoma or a solid tumor cancer.

In an embodiment, the invention provides a pharmaceutical compositioncomprising a PI3K-δ inhibitor and a BTK inhibitor in combination for usein the treatment of leukemia, lymphoma or a solid tumor cancer.

In an embodiment, the invention provides a pharmaceutical compositioncomprising a PI3K-γ,δ inhibitor and a BTK inhibitor in combination foruse in the treatment of leukemia, lymphoma or a solid tumor cancer.

In an embodiment, the invention provides a kit comprising a compositioncomprising a PI3K inhibitor and a composition comprising a BTKinhibitor. These compositions are typically both pharmaceuticalcompositions. The kit is for co-administration of the PI3K inhibitor andthe BTK inhibitor, either simultaneously or separately.

In an embodiment, the invention provides a kit comprising a compositioncomprising a PI3K-γ inhibitor and a composition comprising a BTKinhibitor. These compositions are typically both pharmaceuticalcompositions. The kit is for co-administration of the PI3K-γ inhibitorand the BTK inhibitor, either simultaneously or separately.

In an embodiment, the invention provides a kit comprising a compositioncomprising a PI3K-δ inhibitor and a composition comprising a BTKinhibitor. These compositions are typically both pharmaceuticalcompositions. The kit is for co-administration of the PI3K-δ inhibitorand the BTK inhibitor, either simultaneously or separately.

In an embodiment, the invention provides a kit comprising a compositioncomprising a PI3K-γ,δ inhibitor and a composition comprising a BTKinhibitor. These compositions are typically both pharmaceuticalcompositions. The kit is for co-administration of the PI3K-γ,δ inhibitorand the BTK inhibitor, either simultaneously or separately.

In an embodiment, the invention provides a kit comprising a compositioncomprising a PI3K inhibitor and a composition comprising a BTK inhibitorfor use in the treatment of leukemia, lymphoma or a solid tumor cancer.The compositions are typically both pharmaceutical compositions. The kitis for use in co-administration of the PI3K inhibitor and the BTKinhibitor, either simultaneously or separately, in the treatment ofleukemia, lymphoma or a solid tumor cancer.

In an embodiment, the invention provides a kit comprising a compositioncomprising a PI3K-γ inhibitor and a composition comprising a BTKinhibitor for use in the treatment of leukemia, lymphoma or a solidtumor cancer. The compositions are typically both pharmaceuticalcompositions. The kit is for use in co-administration of the PI3K-γinhibitor and the BTK inhibitor, either simultaneously or separately, inthe treatment of leukemia, lymphoma or a solid tumor cancer.

In an embodiment, the invention provides a kit comprising a compositioncomprising a PI3K-δ inhibitor and a composition comprising a BTKinhibitor for use in the treatment of leukemia, lymphoma or a solidtumor cancer. The compositions are typically both pharmaceuticalcompositions. The kit is for use in co-administration of the PI3K-δinhibitor and the BTK inhibitor, either simultaneously or separately, inthe treatment of leukemia, lymphoma or a solid tumor cancer.

In an embodiment, the invention provides a kit comprising a compositioncomprising a PI3K-γ,δ inhibitor and a composition comprising a BTKinhibitor for use in the treatment of leukemia, lymphoma or a solidtumor cancer. The compositions are typically both pharmaceuticalcompositions. The kit is for use in co-administration of the PI3K-γ,δinhibitor and the BTK inhibitor, either simultaneously or separately, inthe treatment of leukemia, lymphoma or a solid tumor cancer.

In an embodiment, the invention provides a method of treating leukemia,lymphoma or a solid tumor cancer in a subject, comprisingco-administering to a mammal in need thereof a therapeutically effectiveamount of a PI3K inhibitor and a BTK inhibitor.

In an embodiment, the invention provides a method of treating leukemia,lymphoma or a solid tumor cancer in a subject, comprisingco-administering to a mammal in need thereof a therapeutically effectiveamount of a PI3K-γ inhibitor and a BTK inhibitor.

In an embodiment, the invention provides a method of treating leukemia,lymphoma or a solid tumor cancer in a subject, comprisingco-administering to a mammal in need thereof a therapeutically effectiveamount of a PI3K-δ inhibitor and a BTK inhibitor.

In an embodiment, the invention provides a method of treating leukemia,lymphoma or a solid tumor cancer in a subject, comprisingco-administering to a mammal in need thereof a therapeutically effectiveamount of a PI3K-γ,δ inhibitor and a BTK inhibitor.

The BTK inhibitor, in one specific embodiment, is a compound of Formula(XVIII), or a pharmaceutically acceptable salt thereof. The PI3Kinhibitor, in one specific embodiment, is a PI3K-δ inhibitor, inparticular a compound of Formula IX, or a pharmaceutically acceptablesalt thereof. In one specific embodiment, the BTK inhibitor is acompound of Formula (XVIII) or a pharmaceutically acceptable saltthereof, and the PI3K inhibitor is a PI3K-δ inhibitor, in particular acompound of Formula IX, or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofthe invention, will be better understood when read in conjunction withthe appended drawings.

FIG. 1 illustrates the sensitivity of the TMD8 diffuse large B celllymphoma (DLBCL) cell line to individual treatment with the BTKinhibitor of Formula XVIII (“Tested Btk Inhibitor”) and the PI3Kinhibitor of Formula IX (“Tested PI3K Inhibitor”) and combined treatmentwith Formula XVIII and Formula IX (“Btki+PI3Ki”) at differentconcentrations. The concentration of the first agent in the combination(the BTK inhibitor) and the concentration of the individual agents isgiven on the x-axis, and the concentration of the added PI3K inhibitorin combination with the BTK inhibitor is given in the legend.

FIG. 2 illustrates the sensitivity of the MINO mantle cell lymphoma cellto individual treatment with the BTK inhibitor of Formula XVIII (“TestedBtk Inhibitor”) and the PI3K inhibitor of Formula IX (“Tested PI3KInhibitor”) and combined treatment with Formula XVIII and Formula IX(“Btki+PI3Ki”) at different concentrations. The concentration of thefirst agent in the combination (the BTK inhibitor) and the concentrationof the individual agents is given on the x-axis, and the concentrationof the added PI3K inhibitor in combination with the BTK inhibitor isgiven in the legend.

FIG. 3 illustrates the proliferative activity in primary mantle celllymphoma cells of Formula XVIII (“Tested Btki”) and Formula IX (“TestedPI3Ki”). The percentage viability of cells (“% viability”, y-axis) isplotted versus the concentration of the Formula XVIII (“[Tested BtkInhibitor]”, x-axis). The concentration of the individual BTK and PI3Kinhibitors (i.e. not in combination) are also given on the x-axis.

FIG. 4 illustrates the interaction index of the combination of the BTKinhibitor of Formula XVIII and the PI3K inhibitor of Formula IX inprimary mantle cell lymphoma cells.

FIG. 5 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) are combined. The tested cell lines include Maver-1 (B celllymphoma, mantle), Jeko (B cell lymphoma, mantle), CCRF (B lymphoblast,acute lymphoblastic leukemia), and SUP-B15 (B lymphoblast, acutelymphoblastic leukemia). The dose-effect curves for these cell lines aregiven in FIG. 6, FIG. 7, FIG. 8, and FIG. 9. ED25, ED50, ED75, and ED90refer to the effective doses causing 25%, 50%, 75%, and 90% of themaximum biological effect (proliferation).

FIG. 6 illustrates the dose-effect curves obtained for the testedMaver-1 cell line (B cell lymphoma, mantle) using combined dosing of theBTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 7 illustrates the dose-effect curves obtained for the tested Jekocell line (B cell lymphoma, mantle) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 8 illustrates the dose-effect curves obtained for the tested CCRFcell line (B lymphoblast, acute lymphoblastic leukemia) using combineddosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δinhibitor of Formula (IX) (“Inh.3”). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 9 illustrates the dose-effect curves obtained for the testedSUP-B15 cell line (B lymphoblast, acute lymphoblastic leukemia) usingcombined dosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) andthe PI3K-δ inhibitor of Formula (IX) (“Inh.3”). The y-axis (“Effect”) isgiven in units of Fa (fraction affected) and the x-axis (“Dose”) isgiven in linear units of μM.

FIG. 10 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) are combined. The tested cell lines include Jeko (B cell lymphoma,mantle cell lymphoma) and SU-DHL-4 (activated B cell like (ABC) diffuselarge B cell lymphoma). The dose-effect curves for these cell lines aregiven in FIG. 11 and FIG. 12.

FIG. 11 illustrates the dose-effect curves obtained for the tested Jekocell line (B cell lymphoma, mantle) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 12 illustrates the dose-effect curves obtained for the testedSU-DHL-4 cell line (diffuse large B cell lymphoma, ABC) using combineddosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δinhibitor of Formula (IX) (“Inh.3”). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 13 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) are combined. The tested cell lines include CCRF (B lymphoblast,acute lymphoblastic leukemia), SUP-B15 (B lymphoblast, acutelymphoblastic leukemia), JVM-2 (prolymphocytic leukemia), Ramos(Burkitt's lymphoma), and Mino (mantle cell lymphoma). The dose-effectcurves for these cell lines are given in FIG. 14, FIG. 15, FIG. 16, andFIG. 17. No dose-effect curve is given for Ramos (Burkitt's lymphoma)because of negative slope.

FIG. 14 illustrates the dose-effect curves obtained for the tested CCRFcell line (B lymphoblast, acute lymphoblastic leukemia) using combineddosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δinhibitor of Formula (IX) (“Inh.3”). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 15 illustrates the dose-effect curves obtained for the testedSUP-B15 cell line (B lymphoblast, acute lymphoblastic leukemia) usingcombined dosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) andthe PI3K-δ inhibitor of Formula (IX) (“Inh.3”). The y-axis (“Effect”) isgiven in units of Fa (fraction affected) and the x-axis (“Dose”) isgiven in linear units of μM.

FIG. 16 illustrates the dose-effect curves obtained for the tested JVM-2cell line (prolymphocytic leukemia) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 17 illustrates the dose-effect curves obtained for the tested Minocell line (mantle cell lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 18 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) are combined. The tested cell lines include Raji (B lymphocyte,Burkitt's lymphoma), SU-DHL-1 (DLBCL-ABC), and Pfeiffer (follicularlymphoma). The dose-effect curves for these cell lines are given in FIG.19, FIG. 20, and FIG. 21.

FIG. 19 illustrates the dose-effect curves obtained for the tested Rajicell line (B lymphocyte, Burkitt's lymphoma) using combined dosing ofthe BTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitorof Formula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 20 illustrates the dose-effect curves obtained for the testedSU-DHL-1 cell line (DLBCL-ABC) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 21 illustrates the dose-effect curves obtained for the testedPfeiffer cell line (follicular lymphoma) using combined dosing of theBTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 22 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) are combined. The tested cell lines include Ly1 (Germinal centerB-cell like diffuse large B-cell lymphoma, DLBCL-GCB), Ly7 (DLBCL-GCB),Ly19 (DLBCL-GCB), SU-DHL-2 (Activated B-cell like diffuse large B-celllymphoma, DLBCL-ABC), and DOHH2 (follicular lymphoma, FL). Thedose-effect curves for these cell lines are given in FIG. 23, FIG. 24,FIG. 25, and FIG. 26, except for the Ly19 cell line, which is notgraphed because of a negative slope.

FIG. 23 illustrates the dose-effect curves obtained for the tested Ly1cell line (DLBCL-GCB) using combined dosing of the BTK inhibitor ofFormula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor of Formula (IX)(“Inh.3”). The y-axis (“Effect”) is given in units of Fa (fractionaffected) and the x-axis (“Dose”) is given in linear units of μM.

FIG. 24 illustrates the dose-effect curves obtained for the tested Ly7cell line (DLBCL-GCB) using combined dosing of the BTK inhibitor ofFormula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor of Formula (IX)(“Inh.3”). The y-axis (“Effect”) is given in units of Fa (fractionaffected) and the x-axis (“Dose”) is given in linear units of μM.

FIG. 25 illustrates the dose-effect curves obtained for the tested DOHH2cell line (FL) using combined dosing of the BTK inhibitor of Formula(XVIII) (“Inh.1”) and the PI3K-δ inhibitor of Formula (IX) (“Inh.3”).The y-axis (“Effect”) is given in units of Fa (fraction affected) andthe x-axis (“Dose”) is given in linear units of μM.

FIG. 26 illustrates the dose-effect curves obtained for the testedSU-DHL-2 cell line (DLBCL-ABC) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 27 illustrates the synergy observed in certain cell lines whenFormula (XVIII) and Formula (IX) are combined. The tested cell linesinclude U937 (histiocytic lymphoma and/or myeloid), K562 (leukemia,myeloid, and/or chronic myelogenous leukemia), Daudi (human Burkitt'slymphoma), and SU-DHL-6 (DLBCL-GCB and/or peripheral T-cell lymphoma,PTCL). The dose-effect curves for these cell lines are given in FIG. 28,FIG. 29, FIG. 30, and FIG. 31.

FIG. 28 illustrates the dose-effect curves obtained for the tested U937cell line (histiocytic lymphoma and/or myeloid) using combined dosing ofthe BTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitorof Formula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 29 illustrates the dose-effect curves obtained for the tested K562cell line (leukemia, myeloid, and/or chronic myelogenous leukemia) usingcombined dosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) andthe PI3K-δ inhibitor of Formula (IX) (“Inh.3”). The y-axis (“Effect”) isgiven in units of Fa (fraction affected) and the x-axis (“Dose”) isgiven in linear units of μM.

FIG. 30 illustrates the dose-effect curves obtained for the tested Daudicell line (human Burkitt's lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 31 illustrates the dose-effect curves obtained for the testedSU-DHL-6 cell line (DLBCL-GCB and/or PTCL) using combined dosing of theBTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 32 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) are combined. The tested cell lines include SU-DHL-6 (DLBCL-GCB orPTCL), TMD-8 (DLBCL-ABC), HBL-1 (DLBCL-ABC), and Rec-1 (follicularlymphoma). The dose-effect curves for these cell lines are given in FIG.34, FIG. 35, FIG. 36, and FIG. 37.

FIG. 33 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) are combined. The tested cell lines include SU-DHL-6 (DLBCL-GCB orPTCL), TMD-8 (DLBCL-ABC), HBL-1 (DLBCL-ABC), and Rec-1 (follicularlymphoma). All corresponding CIs are shown for each of the combinationstested as listed on the x axis.

FIG. 34 illustrates the dose-effect curves obtained for the testedSU-DHL-6 cell line (DLBCL-GCB or PTCL) cell line using combined dosingof the BTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δinhibitor of Formula (IX) (“Inh.3”). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 35 illustrates the dose-effect curves obtained for the tested TMD-8cell line (DLBCL-ABC) using combined dosing of the BTK inhibitor ofFormula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor of Formula (IX)(“Inh.3”). The y-axis (“Effect”) is given in units of Fa (fractionaffected) and the x-axis (“Dose”) is given in linear units of μM.

FIG. 36 illustrates the dose-effect curves obtained for the tested HBL-1cell line (DLBCL-ABC) using combined dosing of the BTK inhibitor ofFormula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor of Formula (IX)(“Inh.3”). The y-axis (“Effect”) is given in units of Fa (fractionaffected) and the x-axis (“Dose”) is given in linear units of μM.

FIG. 37 illustrates the dose-effect curves obtained for the tested Rec-1cell line (follicular lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 38 illustrates tumor growth suppression in an orthotopic pancreaticcancer model. Mice were dosed orally with 15 mg/kg of the BTK inhibitorof Formula (XVIII), 15 mg/kg of the PI3K-δ inhibitor of Formula (IX), ora combination of both drugs. The statistical p-value (presumptionagainst null hypothesis) is shown for each tested single agent and forthe combination against the vehicle.

FIG. 39 illustrates the effects of oral dosing with 15 mg/kg of the BTKinhibitor of Formula (XVIII), 15 mg/kg of the PI3K-δ inhibitor ofFormula (IX), or a combination of both inhibitors on myeloidtumor-associated macrophages (TAMs) in pancreatic tumor-bearing mice.

FIG. 40 illustrates the effects of oral dosing with 15 mg/kg of the BTKinhibitor of Formula (XVIII), 15 mg/kg of the PI3K-δ inhibitor ofFormula (IX), or a combination of both inhibitors on myeloid-derivedsuppressor cells (MDSCs) in pancreatic tumor-bearing mice.

FIG. 41 illustrates the effects of oral dosing with 15 mg/kg of the BTKinhibitor of Formula (XVIII), 15 mg/kg of the PI3K-δ inhibitor ofFormula (IX), or a combination of both inhibitors on regulatory T cells(Tregs) in pancreatic tumor-bearing mice.

FIG. 42 illustrates the effects of vehicle on flux at two timepoints, asa control for comparison with FIG. 100, in the ID8 syngeneic orthotropicovarian cancer model.

FIG. 43 illustrates the effects of the BTK inhibitor of Formula (XVIII)on flux at two timepoints, for comparison with FIG. 99, in the ID8syngeneic orthotropic ovarian cancer model.

FIG. 44 illustrates tumor response to treatment with the BTK inhibitorof Formula (XVIII) correlates with a significant reduction inimmunosuppressive tumor associated lymphocytes in tumor-bearing mice, incomparison to a control (vehicle).

FIG. 45 illustrates that treatment with the BTK inhibitor of Formula(XVIII) impairs ID8 ovarian cancer growth in the syngeneic murine modelin comparison to a control (vehicle).

FIG. 46 illustrates that treatment with the BTK inhibitor of Formula(XVIII) induces a tumor response that correlates with a significantreduction in total B cells in tumor-bearing mice.

FIG. 47 illustrates that treatment with the BTK inhibitor of Formula(XVIII) induces a tumor response that correlates with a significantreduction in B regulatory cells (Bregs) in tumor-bearing mice.

FIG. 48 illustrates that treatment with the BTK inhibitor of Formula(XVIII) induces a tumor response that correlates with a significantreduction in immunosuppressive tumor associated Tregs.

FIG. 49 illustrates that treatment with the BTK inhibitor of Formula(XVIII) induces a tumor response that correlates with an increase inCD8⁺ T cells.

FIG. 50 illustrates the effects on tumor volume of vehicle (measured inmm³) of the BTK inhibitor of Formula (XVIII), a combination of the BTKinhibitor of Formula (XVIII) and gemcitabine (“Gem”), and gemcitabinealone.

FIG. 51 illustrates the effects on the amount of CD8⁺ T cells, given asa percentage of cells expressing the T cell receptor (CD3), of the BTKinhibitor of Formula (XVIII), a combination of the BTK inhibitor ofFormula (XVIII) and gemcitabine (“Gem”), and gemcitabine alone.

FIG. 52 illustrates the effects on the percentage of CD4⁺, CD25⁺, andFoxP3⁺ T regulatory cells (“Tregs”), given as a percentage of cellsexpressing the T cell receptor (CD3), of the BTK inhibitor of Formula(XVIII), a combination of the BTK inhibitor of Formula (XVIII) andgemcitabine (“Gem”), and gemcitabine alone.

FIG. 53 illustrates the effects on the percentage of CD11b⁺, LY6C^(low),F4/80⁺, and Csflr⁺ tumor-associated macrophages (“TAMs”), given as apercentage of cells expressing the T cell receptor (CD3), of the BTKinhibitor of Formula (XVIII), a combination of the BTK inhibitor ofFormula (XVIII) and gemcitabine (“Gem”), and gemcitabine alone.

FIG. 54 illustrates the effects on the percentage of Gr1⁺ and LY6C^(hi),F4/80⁺, and Csflr⁺ myeloid-derived suppressor cells (“MDSCs”), given asa percentage of cells expressing the T cell receptor (CD3), of the BTKinhibitor of Formula (XVIII), a combination of the BTK inhibitor ofFormula (XVIII) and gemcitabine (“Gem”), and gemcitabine alone.

FIG. 55 illustrates representative photomicrographs and comparison ofmaximal thrombus size in laser injured arterioles of VWF HA1 mutant miceinfused with human platelets in the absence or presence of various BTKinhibitors. Representative photomicrographs are given as a comparison ofmaximal thrombus size in laser-injured arterioles (1 μM concentrationsshown).

FIG. 56 illustrates a quantitative comparison obtained by in vivoanalysis of early thrombus dynamics in a humanized mouse laser injurymodel using three BTK inhibitors at a concentration 1 μM.

FIG. 57 illustrates the effect of the tested BTK inhibitors on thrombusformation. The conditions used were N=4, 3 mice per drug; anti-clottingagents <2000 μM². In studies with ibrutinib, 48% MCL bleeding eventswere observed with 560 mg QD and 63% CLL bleeding events were observedwith 420 mg QD, where bleeding event is defined as subdural hematoma,ecchymoses, GI bleeding, or hematuria.

FIG. 58 illustrates the effect of the concentration of the tested BTKinhibitors on thrombus formation.

FIG. 59 illustrates the results of GPVI platelet aggregation studies ofFormula XVIII (IC50=1.15 μM) and Formula XX-A (ibrutinib, IC50=0.13 μM).

FIG. 60 illustrates the results of GPVI platelet aggregation studies ofFormula XVIII and Formula XX-A (ibrutinib).

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs.

The terms “co-administration” and “administered in combination with” asused herein, encompass administration of two or more agents (such as atleast one PI3K inhibitor and at least one BTK inhibitor) to a subject(such as a human or a mammal), so that both agents and/or theirmetabolites are present in the subject at the same time. Agents are alsoreferred to as active ingredients, or active pharmaceutical ingredients,or drugs. Co-administration includes simultaneous administration inseparate compositions (also referred to as concurrent administration),administration at different times in separate compositions, oradministration in a composition in which both agents are present.Simultaneous administration in separate compositions and administrationin a composition in which both agents are present are preferred.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound or combination of compounds as describedherein that is sufficient to effect the intended application including,but not limited to, disease treatment. A therapeutically effectiveamount may vary depending upon the intended application (in vitro or invivo), or the subject and disease condition being treated (e.g., theweight, age and gender of the subject), the severity of the diseasecondition, the manner of administration, etc. which can readily bedetermined by one of ordinary skill in the art. The term also applies toa dose that will induce a particular response in target cells, (e.g.,the reduction of platelet adhesion and/or cell migration). The specificdose will vary depending on the particular compounds chosen, the dosingregimen to be followed, whether the compound is administered incombination with other compounds, timing of administration, the tissueto which it is administered, and the physical delivery system in whichthe compound is carried.

A “therapeutic effect” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit. A prophylactic effectincludes delaying or eliminating the appearance of a disease orcondition, delaying or eliminating the onset of symptoms of a disease orcondition, slowing, halting, or reversing the progression of a diseaseor condition, or any combination thereof.

The term “pharmaceutically acceptable salt” refers to salts derived froma variety of organic and inorganic counter ions known in the art.Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Inorganic acids from which salts canbe derived include, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid and phosphoric acid. Organic acids from whichsalts can be derived include, for example, acetic acid, propionic acid,glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid and salicylic acid. Pharmaceutically acceptablebase addition salts can be formed with inorganic and organic bases.Inorganic bases from which salts can be derived include, for example,sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc,copper, manganese and aluminum. Organic bases from which salts can bederived include, for example, primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins. Specific examples includeisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine. In selected embodiments, thepharmaceutically acceptable base addition salt is chosen from ammonium,potassium, sodium, calcium, and magnesium salts.

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” is intended to include any and all solvents, dispersionmedia, coatings, antibacterial and antifungal agents, isotonic andabsorption delaying agents, and inert ingredients. The use of suchpharmaceutically acceptable carriers or pharmaceutically acceptableexcipients for active pharmaceutical ingredients is well known in theart. Except insofar as any conventional pharmaceutically acceptablecarrier or pharmaceutically acceptable excipient is incompatible withthe active pharmaceutical ingredient, its use in the therapeuticcompositions of the invention is contemplated. Supplementary activepharmaceutical ingredients, such as other drugs, can also beincorporated into the described compositions and methods.

“Prodrug” is intended to describe a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers the advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, e.g., Bundgaard, H., Design of Prodrugs (1985) (Elsevier,Amsterdam). The term “prodrug” is also intended to include anycovalently bonded carriers, which release the active compound in vivowhen administered to a subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to yield the active parentcompound. Prodrugs include, for example, compounds wherein a hydroxy,amino or mercapto group is bonded to any group that, when the prodrug ofthe active compound is administered to a mammalian subject, cleaves toform a free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetates, formatesand benzoate derivatives of an alcohol, various ester derivatives of acarboxylic acid, or acetamide, formamide and benzamide derivatives of anamine functional group in the active compound.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. In vitro assays encompass cell-based assays in whichcells alive or dead are employed and may also encompass a cell-freeassay in which no intact cells are employed.

Unless otherwise stated, the chemical structures depicted herein areintended to include compounds which differ only in the presence of oneor more isotopically enriched atoms. For example, compounds where one ormore hydrogen atoms is replaced by deuterium or tritium, or wherein oneor more carbon atoms is replaced by ¹³C- or ¹⁴C-enriched carbons, arewithin the scope of this invention.

When ranges are used herein to describe, for example, physical orchemical properties such as weight or chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. Use of the term “about” whenreferring to a number or a numerical range means that the number ornumerical range referred to is an approximation within experimentalvariability (or within statistical experimental error), and thus thenumber or numerical range may vary. The variation is typically from 0%to 10%, preferably from 0% to 10%, more preferably from 0% to 5% of thestated number or numerical range. The term “comprising” (and relatedterms such as “comprise” or “comprises” or “having” or “including”)encompasses those embodiments such as, for example, an embodiment of anycomposition of matter, method or process that “consist of” or “consistessentially of” the described features.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten carbon atoms (i.e., C₁-C₁₀alkyl and(C₁-C₁₀)alkyl). Whenever it appears herein, a numerical range such as “1to 10” refers to each integer in the given range—e.g., “1 to 10 carbonatoms” means that the alkyl group may consist of 1 carbon atom, 2 carbonatoms, 3 carbon atoms, etc., up to and including 10 carbon atoms,although the definition is also intended to cover the occurrence of theterm “alkyl” where no numerical range is specifically designated.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl,tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,nonyl and decyl. The alkyl moiety may be attached to the rest of themolecule by a single bond, such as for example, methyl (Me), ethyl (Et),n-propyl (Pr), 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl) and 3-methylhexyl. Unless stated otherwisespecifically in the specification, an alkyl group is optionallysubstituted by one or more of substituents which are independentlyalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂ whereeach R^(a) is independently hydrogen, unsubstituted alkyl, fluoroalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl areas disclosed herein and which are optionally substituted by one or moreof the substituents described as suitable substituents for aryl andalkyl respectively.

“Alkylhetaryl” refers to an -(alkyl)hetaryl radical where hetaryl andalkyl are as disclosed herein and which are optionally substituted byone or more of the substituents described as suitable substituents foraryl and alkyl respectively.

“Alkylheterocycloalkyl” refers to an -(alkyl) heterocycyl radical wherealkyl and heterocycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heterocycloalkyl and alkyl respectively.

An “alkene” moiety refers to a group consisting of at least two carbonatoms and at least one carbon-carbon double bond, and an “alkyne” moietyrefers to a group consisting of at least two carbon atoms and at leastone carbon-carbon triple bond. The alkyl moiety, whether saturated orunsaturated, may be branched, straight chain, or cyclic.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to ten carbon atoms (i.e.,C₂-C₁₀ alkenyl and (C₂-C₁₀)alkenyl). Whenever it appears herein, anumerical range such as “2 to 10” refers to each integer in the givenrange—e.g., “2 to 10 carbon atoms” means that the alkenyl group mayconsist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10carbon atoms. The alkenyl moiety may be attached to the rest of themolecule by a single bond, such as for example, ethenyl (i.e., vinyl),prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl and penta-1,4-dienyl.Unless stated otherwise specifically in the specification, an alkenylgroup is optionally substituted by one or more substituents which areindependently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkenyl-cycloalkyl” refers to an (alkenyl)cycloalkyl radical wherealkenyl and cycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for alkenyl and cycloalkyl respectively.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to ten carbon atoms (i.e. C₂-C₁₀alkynyl and (C₂-C₁₀)alkynyl). Whenever it appears herein, a numericalrange such as “2 to 10” refers to each integer in the given range—e.g.,“2 to 10 carbon atoms” means that the alkynyl group may consist of 2carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.The alkynyl may be attached to the rest of the molecule by a singlebond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl.Unless stated otherwise specifically in the specification, an alkynylgroup is optionally substituted by one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkynyl-cycloalkyl” refers to an -(alkynyl)cycloalkyl radical wherealkynyl and cycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for alkynyl and cycloalkyl respectively.

“Carboxaldehyde” refers to a —(C═O)H radical.

“Carboxyl” refers to a —(C═O)OH radical.

“Cyano” refers to a —CN radical.

“Cycloalkyl” refers to a monocyclic or polycyclic radical that containsonly carbon and hydrogen, and may be saturated, or partiallyunsaturated. Cycloalkyl groups include groups having from 3 to 10 ringatoms (i.e. C₂-C₁₀ cycloalkyl and (C₂-C₁₀)cycloalkyl). Whenever itappears herein, a numerical range such as “3 to 10” refers to eachinteger in the given range—e.g., “3 to 10 carbon atoms” means that thecycloalkyl group may consist of 3 carbon atoms and greater, up to andincluding 10 carbon atoms. Illustrative examples of cycloalkyl groupsinclude, but are not limited to the following moieties: cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbomyl, and the like.Unless stated otherwise specifically in the specification, a cycloalkylgroup is optionally substituted by one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Cycloalkyl-alkenyl” refers to a -(cycloalkyl)alkenyl radical wherecycloalkyl and alkenyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for cycloalkyl and alkenyl, respectively.

“Cycloalkyl-heterocycloalkyl” refers to a -(cycloalkyl)heterocycloalkylradical where cycloalkyl and heterocycloalkyl are as disclosed hereinand which are optionally substituted by one or more of the substituentsdescribed as suitable substituents for cycloalkyl and heterocycloalkyl,respectively.

“Cycloalkyl-heteroaryl” refers to a -(cycloalkyl)heteroaryl radicalwhere cycloalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for cycloalkyl and heteroaryl, respectively.

The term “alkoxy” refers to the group —O-alkyl, including from 1 to 8carbon atoms of a straight, branched, cyclic configuration andcombinations thereof attached to the parent structure through an oxygen.Examples include, but are not limited to, methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy and cyclohexyloxy. “Lower alkoxy” refers toalkoxy groups containing one to six carbons.

The term “substituted alkoxy” refers to alkoxy wherein the alkylconstituent is substituted (i.e., —O-(substituted alkyl)). Unless statedotherwise specifically in the specification, the alkyl moiety of analkoxy group is optionally substituted by one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term “alkoxycarbonyl” refers to a group of the formula(alkoxy)(C═O)— attached through the carbonyl carbon wherein the alkoxygroup has the indicated number of carbon atoms. Thus a C₁-C₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atomsattached through its oxygen to a carbonyl linker. “Lower alkoxycarbonyl”refers to an alkoxycarbonyl group wherein the alkoxy group is a loweralkoxy group.

The term “substituted alkoxycarbonyl” refers to the group (substitutedalkyl)-O—C(O)— wherein the group is attached to the parent structurethrough the carbonyl functionality. Unless stated otherwise specificallyin the specification, the alkyl moiety of an alkoxycarbonyl group isoptionally substituted by one or more substituents which independentlyare: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Acyl” refers to the groups (alkyl)-C(O)—, (aryl)-C(O)—,(heteroaryl)-C(O)—, (heteroalkyl)-C(O)— and (heterocycloalkyl)-C(O)—,wherein the group is attached to the parent structure through thecarbonyl functionality. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms. Unless stated otherwise specifically inthe specification, the alkyl, aryl or heteroaryl moiety of the acylgroup is optionally substituted by one or more substituents which areindependently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Acyloxy” refers to a R(C═O)O— radical wherein “R” is alkyl, aryl,heteroaryl, heteroalkyl or heterocycloalkyl, which are as describedherein. If the R radical is heteroaryl or heterocycloalkyl, the heteroring or chain atoms contribute to the total number of chain or ringatoms. Unless stated otherwise specifically in the specification, the“R” of an acyloxy group is optionally substituted by one or moresubstituents which independently are: alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Amino” or “amine” refers to a —N(R^(a))₂ radical group, where eachR^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless statedotherwise specifically in the specification. When a —N(R^(a))₂ group hastwo R^(a) substituents other than hydrogen, they can be combined withthe nitrogen atom to form a 4-, 5-, 6- or 7-membered ring. For example,—N(R^(a))₂ is intended to include, but is not limited to, 1-pyrrolidinyland 4-morpholinyl. Unless stated otherwise specifically in thespecification, an amino group is optionally substituted by one or moresubstituents which independently are: alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term “substituted amino” also refers to N-oxides of the groups—NHR^(d), and NR^(d)R^(d) each as described above. N-oxides can beprepared by treatment of the corresponding amino group with, forexample, hydrogen peroxide or m-chloroperoxybenzoic acid.

“Amide” or “amido” refers to a chemical moiety with formula —C(O)N(R)₂or —NHC(O)R, where R is selected from the group consisting of hydrogen,alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), each of which moiety mayitself be optionally substituted. The R₂ of —N(R)₂ of the amide mayoptionally be taken together with the nitrogen to which it is attachedto form a 4-, 5-, 6- or 7-membered ring. Unless stated otherwisespecifically in the specification, an amido group is optionallysubstituted independently by one or more of the substituents asdescribed herein for alkyl, cycloalkyl, aryl, heteroaryl, orheterocycloalkyl. An amide may be an amino acid or a peptide moleculeattached to a compound of Formula (I), thereby forming a prodrug. Theprocedures and specific groups to make such amides, including the use ofprotecting groups, are known to those of skill in the art and canreadily be found in seminal sources such as Greene and Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York,N.Y., 1999.

“Aromatic” or “aryl” or “Ar” refers to an aromatic radical with six toten ring atoms (e.g., C₆-C₁₀ aromatic or C₆-C₁₀ aryl) which has at leastone ring having a conjugated pi electron system which is carbocyclic(e.g., phenyl, fluorenyl, and naphthyl). Bivalent radicals formed fromsubstituted benzene derivatives and having the free valences at ringatoms are named as substituted phenylene radicals. Bivalent radicalsderived from univalent polycyclic hydrocarbon radicals whose names endin “-yl” by removal of one hydrogen atom from the carbon atom with thefree valence are named by adding “-idene” to the name of thecorresponding univalent radical, e.g., a naphthyl group with two pointsof attachment is termed naphthylidene. Whenever it appears herein, anumerical range such as “6 to 10” refers to each integer in the givenrange; e.g., “6 to 10 ring atoms” means that the aryl group may consistof 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms.The term includes monocyclic or fused-ring polycyclic (i.e., rings whichshare adjacent pairs of ring atoms) groups. Unless stated otherwisespecifically in the specification, an aryl moiety is optionallysubstituted by one or more substituents which are independently alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl andalkyl are as disclosed herein and which are optionally substituted byone or more of the substituents described as suitable substituents foraryl and alkyl respectively.

“Ester” refers to a chemical radical of formula —COOR, where R isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heteroalicyclic (bondedthrough a ring carbon). The procedures and specific groups to makeesters, including the use of protecting groups, are known to those ofskill in the art and can readily be found in seminal sources such asGreene and Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed.,John Wiley & Sons, New York, N.Y., 1999. Unless stated otherwisespecifically in the specification, an ester group is optionallysubstituted by one or more substituents which independently are: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of thefluoroalkyl radical may be optionally substituted as defined above foran alkyl group.

“Halo,” “halide,” or, alternatively, “halogen” is intended to meanfluoro, chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,”“haloalkynyl,” and “haloalkoxy” include alkyl, alkenyl, alkynyl andalkoxy structures that are substituted with one or more halo groups orwith combinations thereof. For example, the terms “fluoroalkyl” and“fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, inwhich the halo is fluorine.

“Heteroalkyl,” “heteroalkenyl,” and “heteroalkynyl” refer to optionallysubstituted alkyl, alkenyl and alkynyl radicals and which have one ormore skeletal chain atoms selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Anumerical range may be given—e.g., C₁-C₄ heteroalkyl which refers to thechain length in total, which in this example is 4 atoms long. Aheteroalkyl group may be substituted with one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Heteroalkylaryl” refers to an -(heteroalkyl)aryl radical whereheteroalkyl and aryl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and aryl, respectively.

“Heteroalkylheteroaryl” refers to an -(heteroalkyl)heteroaryl radicalwhere heteroalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and heteroaryl, respectively.

“Heteroalkylheterocycloalkyl” refers to an-(heteroalkyl)heterocycloalkyl radical where heteroalkyl andheterocycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and heterocycloalkyl, respectively.

“Heteroalkylcycloalkyl” refers to an -(heteroalkyl)cycloalkyl radicalwhere heteroalkyl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and cycloalkyl, respectively.

“Heteroaryl” or “heteroaromatic” or “HetAr” refers to a 5- to18-membered aromatic radical (e.g., C₅-C₁₃ heteroaryl) that includes oneor more ring heteroatoms selected from nitrogen, oxygen and sulfur, andwhich may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem. Whenever it appears herein, a numerical range such as “5 to 18”refers to each integer in the given range—e.g., “5 to 18 ring atoms”means that the heteroaryl group may consist of 5 ring atoms, 6 ringatoms, etc., up to and including 18 ring atoms. Bivalent radicalsderived from univalent heteroaryl radicals whose names end in “-yl” byremoval of one hydrogen atom from the atom with the free valence arenamed by adding “-idene” to the name of the corresponding univalentradical—e.g., a pyridyl group with two points of attachment is apyridylidene. A N-containing “heteroaromatic” or “heteroaryl” moietyrefers to an aromatic group in which at least one of the skeletal atomsof the ring is a nitrogen atom. The polycyclic heteroaryl group may befused or non-fused. The heteroatom(s) in the heteroaryl radical areoptionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heteroaryl may be attached to the rest ofthe molecule through any atom of the ring(s). Examples of heteroarylsinclude, but are not limited to, azepinyl, acridinyl, benzimidazolyl,benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl,benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl,benzothiazolyl, benzothienyl(benzothiophenyl),benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, aheteroaryl moiety is optionally substituted by one or more substituentswhich are independently: alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

Substituted heteroaryl also includes ring systems substituted with oneor more oxide (—O—) substituents, such as, for example, pyridinylN-oxides.

“Heteroarylalkyl” refers to a moiety having an aryl moiety, as describedherein, connected to an alkylene moiety, as described herein, whereinthe connection to the remainder of the molecule is through the alkylenegroup.

“Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromaticring radical that comprises two to twelve carbon atoms and from one tosix heteroatoms selected from nitrogen, oxygen and sulfur. Whenever itappears herein, a numerical range such as “3 to 18” refers to eachinteger in the given range—e.g., “3 to 18 ring atoms” means that theheterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc.,up to and including 18 ring atoms. Unless stated otherwise specificallyin the specification, the heterocycloalkyl radical is a monocyclic,bicyclic, tricyclic or tetracyclic ring system, which may include fusedor bridged ring systems. The heteroatoms in the heterocycloalkyl radicalmay be optionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heterocycloalkyl radical is partially orfully saturated. The heterocycloalkyl may be attached to the rest of themolecule through any atom of the ring(s). Examples of suchheterocycloalkyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocycloalkyl moiety is optionally substituted byone or more substituents which independently are: alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Heterocycloalkyl” also includes bicyclic ring systems wherein onenon-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2carbon atoms in addition to 1-3 heteroatoms independently selected fromoxygen, sulfur, and nitrogen, as well as combinations comprising atleast one of the foregoing heteroatoms; and the other ring, usually with3 to 7 ring atoms, optionally contains 1-3 heteroatoms independentlyselected from oxygen, sulfur, and nitrogen and is not aromatic.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space—i.e., having a different stereochemical configuration.“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate. “Diastereoisomers” are stereoisomers that have atleast two asymmetric atoms, but which are not mirror-images of eachother. The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer thestereochemistry at each chiral carbon can be specified by either R or S.Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain of the compounds described herein containone or more asymmetric centers and can thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that can be defined, interms of absolute stereochemistry, as (R)- or (S)-. The present chemicalentities, pharmaceutical compositions and methods are meant to includeall such possible isomers, including racemic mixtures, optically pureforms and intermediate mixtures. Optically active (R)- and (S)-isomerscan be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers.

“Enantiomeric purity” as used herein refers to the relative amounts,expressed as a percentage, of the presence of a specific enantiomerrelative to the other enantiomer. For example, if a compound, which maypotentially have an (R)- or an (S)-isomeric configuration, is present asa racemic mixture, the enantiomeric purity is about 50% with respect toeither the (R)- or (S)-isomer. If that compound has one isomeric formpredominant over the other, for example, 80% (S)- and 20% (R)—, theenantiomeric purity of the compound with respect to the (S)-isomericform is 80%. The enantiomeric purity of a compound can be determined ina number of ways known in the art, including but not limited tochromatography using a chiral support, polarimetric measurement of therotation of polarized light, nuclear magnetic resonance spectroscopyusing chiral shift reagents which include but are not limited tolanthanide containing chiral complexes or the Pirkle alcohol, orderivatization of a compounds using a chiral compound such as Mosher'sacid followed by chromatography or nuclear magnetic resonancespectroscopy.

“Moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Tautomers” are structurally distinct isomers that interconvert bytautomerization. “Tautomerization” is a form of isomerization andincludes prototropic or proton-shift tautomerization, which isconsidered a subset of acid-base chemistry. “Prototropictautomerization” or “proton-shift tautomerization” involves themigration of a proton accompanied by changes in bond order, often theinterchange of a single bond with an adjacent double bond. Wheretautomerization is possible (e.g. in solution), a chemical equilibriumof tautomers can be reached. An example of tautomerization is keto-enoltautomerization. A specific example of keto-enol tautomerization is theinterconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-onetautomers. Another example of tautomerization is phenol-ketotautomerization. A specific example of phenol-keto tautomerization isthe interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

The terms “enantiomerically enriched,” “enantiomerically pure” and“non-racemic,” as used herein, refer to compositions in which thepercent by weight of one enantiomer is greater than the amount of thatone enantiomer in a control mixture of the racemic composition (e.g.,greater than 1:1 by weight). For example, an enantiomerically enrichedpreparation of the (S)-enantiomer, means a preparation of the compoundhaving greater than 50% by weight of the (S)-enantiomer relative to the(R)-enantiomer, such as at least 75% by weight, such as at least 80% byweight. In some embodiments, the enrichment can be significantly greaterthan 80% by weight, providing a “substantially enantiomericallyenriched,” “substantially enantiomerically pure” or a “substantiallynon-racemic” preparation, which refers to preparations of compositionswhich have at least 85% by weight of one enantiomer relative to theother enantiomer, such as at least 90% by weight, and such as at least95% by weight. The terms “diastereomerically enriched” and“diastereomerically pure,” as used herein, refer to compositions inwhich the percent by weight of one diastereomer is greater than theamount of that one diastereomer in a control mixture of diastereomers.In some embodiments, the enrichment can be significantly greater than80% by weight, providing a “substantially diastereomerically enriched”or “substantially diastereomerically pure” preparation, which refers topreparations of compositions which have at least 85% by weight of onediastereomer relative to other diastereomers, such as at least 90% byweight, and such as at least 95% by weight.

In preferred embodiments, the enantiomerically enriched composition hasa higher potency with respect to therapeutic utility per unit mass thandoes the racemic mixture of that composition. Enantiomers can beisolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred enantiomerscan be prepared by asymmetric syntheses. See, for example, Jacques, etal., Enantiomers, Racemates and Resolutions, Wiley Interscience, NewYork, 1981; and Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill,N Y, 1962.

A “leaving group or atom” is any group or atom that will, under selectedreaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Examples of such groups, unless otherwisespecified, include halogen atoms and mesyloxy, p-nitrobenzensulphonyloxyand tosyloxy groups.

“Protecting group” is intended to mean a group that selectively blocksone or more reactive sites in a multifunctional compound such that achemical reaction can be carried out selectively on another unprotectedreactive site and the group can then be readily removed after theselective reaction is complete. A variety of protecting groups aredisclosed, for example, in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, Third Edition, John Wiley & Sons, New York,1999.

“Solvate” refers to a compound in physical association with one or moremolecules of a pharmaceutically acceptable solvent.

“Substituted” means that the referenced group may have attached one ormore additional moieties individually and independently selected from,for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl,carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxy, alkoxy,aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester,thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo,perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- anddi-substituted amino groups, and protected derivatives thereof. Thesubstituents themselves may be substituted, for example, a cycloalkylsubstituent may itself have a halide substituent at one or more of itsring carbons. The term “substituted” also means that one or morehydrogens on the designated atom/atoms is/are replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalency under the existing circumstances is not exceeded, and that thesubstitution results in a stable compound. Combinations of substituentsand/or variables are permissible if such combinations result in stablecompounds. “Stable compound” or “stable structure” is defined as acompound or structure that is sufficiently robust to survive isolationto a useful degree of purity from a reaction mixture, and formulationinto an efficacious therapeutic agent. The terms “optionallysubstituted” and “may optionally be substituted” means optionalsubstitution with the specified groups, radicals or moieties.

“Sulfanyl” refers to groups that include —S-(optionally substitutedalkyl), —S-(optionally substituted aryl), ionally substitutedheteroaryl) and —S-(optionally substituted heterocycloalkyl).

“Sulfinyl” refers to groups that include —S(O)—H, —S(O)-(optionallysubstituted alkyl), —S(O)-(optionally substituted amino),—S(O)-(optionally substituted aryl), —S(O)-(optionally substitutedheteroaryl) and —S(O)-(optionally substituted heterocycloalkyl).

“Sulfonyl” refers to groups that include —S(O₂)—H, —S(O₂)-(optionallysubstituted alkyl), —S(O₂)-(optionally substituted amino),—S(O₂)-(optionally substituted aryl), —S(O₂)-(optionally substitutedheteroaryl), and —S(O₂)-(optionally substituted heterocycloalkyl).

“Sulfonamidyl” or “sulfonamido” refers to a —S(═O)₂—NRR radical, whereeach R is selected independently from the group consisting of hydrogen,alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon). The R groups in —NRR ofthe —S(═O)₂—NRR radical may be taken together with the nitrogen to whichit is attached to form a 4-, 5-, 6- or 7-membered ring. A sulfonamidogroup is optionally substituted by one or more of the substituentsdescribed for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

“Sulfoxyl” refers to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂—OR radical, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon) and heteroalicyclic (bonded through a ring carbon). Asulfonate group is optionally substituted on R by one or more of thesubstituents described for alkyl, cycloalkyl, aryl, heteroaryl,respectively.

Compounds of the invention also include crystalline and amorphous formsof those compounds, including, for example, polymorphs,pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (includinganhydrates), conformational polymorphs, and amorphous forms of thecompounds, as well as mixtures thereof. “Crystalline form” and“polymorph” are intended to include all crystalline and amorphous formsof the compound, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms, as well as mixturesthereof, unless a particular crystalline or amorphous form is referredto.

Co-Administration of Compounds

An embodiment of the invention is a composition, such as apharmaceutical composition, comprising a combination of a PI3K inhibitorand a BTK inhibitor. Another embodiment is a kit containing bothcomponents formulated into separate pharmaceutical compositions, whichare formulated for co-administration.

Another embodiment of the invention is a method of treating a disease orcondition in a subject, in particular a hyperproliferative disorder likeleukemia, lymphoma or a solid tumor cancer in a subject, comprisingco-administering to the subject in need thereof a therapeuticallyeffective amount of a combination of a PI3K inhibitor and a BTKinhibitor. The pharmaceutical composition comprising the combination,and the kit, are both for use in treating such disease or condition.

In an exemplary embodiment, the solid tumor cancer is selected from thegroup consisting of breast, lung, colorectal, thyroid, bone sarcoma andstomach cancers.

In an exemplary embodiment, the leukemia is selected from the groupconsisting of acute myelogenous leukemia (AML), chronic myelogenousleukemia (CML), and acute lymphoblastic leukemia (ALL).

In a preferred embodiment, the PI3K inhibitor is a PI3K-γ inhibitor.

In another preferred embodiment, the PI3K inhibitor is a PI3K-δinhibitor.

In another preferred embodiment, the PI3K inhibitor is a PI3K-γ,δinhibitor.

In a particularly preferred embodiment, the PI3K inhibitor is a PI3K-δinhibitor. This PI3K-δ inhibitor is more preferably a compound ofFormula VIII, even more preferably the compound of Formula IX.

The BTK inhibitor is preferably a compound of Formula XVII, even morepreferably the compound of Formula XVIII.

In one specific embodiment, the PI3K inhibitor is a PI3K-δ inhibitor andthe BTK inhibitor is a compound of Formula XVII, even more preferablythe compound of Formula XVIII. In a specifically preferred embodiment,the PI3K inhibitor is the compound of Formula IX and the BTK inhibitoris the compound of Formula XVIII. One or both of said inhibitors mayalso be in the form of a pharmaceutically acceptable salt.

In an exemplary embodiment, the PI3K inhibitor is a PI3K inhibitorselective for 6-PI3K, γ-PI3K, or γ,δ-PI3K isoforms.

The combination may be administered by any route known in the art. In anexemplary embodiment, the combination of the PI3K inhibitor, which ispreferably selected from the group consisting of a PI3K-γ inhibitor, aPI3K-δ inhibitor, and a PI3K-γ,δ inhibitor, with the BTK inhibitor isadministered by oral, intravenous, intramuscular, intraperitoneal,subcutaneous or transdermal means. In one embodiment, the administrationis by injection.

In an exemplary embodiment, the PI3K inhibitor, which is preferablyselected from the group consisting of a PI3K-γ inhibitor, a PI3K-δinhibitor, and a PI3K-γ,δ inhibitor, is in the form of apharmaceutically acceptable salt.

In an exemplary embodiment, the BTK inhibitor is in the form of apharmaceutically acceptable salt.

In an exemplary embodiment, the PI3K inhibitor, which is preferablyselected from the group consisting of a PI3K-γ inhibitor, a PI3K-δinhibitor, and a PI3K-γ,δ inhibitor, is administered to the subjectbefore administration of the BTK inhibitor.

In an exemplary embodiment, the PI3K inhibitor, which is preferablyselected from the group consisting of a PI3K-γ inhibitor, a PI3K-δinhibitor, and a PI3K-γ,δ inhibitor, is administered concurrently withthe administration of the BTK inhibitor.

In an exemplary embodiment, the PI3K inhibitor, which is preferablyselected from the group consisting of a PI3K-γ inhibitor, a PI3K-δinhibitor, and a PI3K-γ,δ inhibitor, is administered to the subjectafter administration of the BTK inhibitor.

In an exemplary embodiment, the subject is a mammal, such as a human.

PI3K Inhibitors

In particular, it is one of the PI3K inhibitors described in more detailin the following paragraphs. Preferably, it is a PI3K inhibitor selectedfrom the group consisting of PI3K-γ inhibitor, PI3K-δ inhibitor, andPI3K-γ,δ inhibitor. In one specific embodiment, it is a PI3K-δinhibitor. In a preferred embodiment, it is a compound of Formula IX ora pharmaceutically acceptable salt thereof.

In an exemplary embodiment, the PI3K inhibitor, which may preferably beselected from the group consisting of PI3K-γ inhibitor, PI3K-δinhibitor, and PI3K-γ,δ inhibitor, is a compound selected from thestructures disclosed in U.S. Pat. Nos. 8,193,182 and 8,569,323, and U.S.Patent Application Publication Nos. 2012/0184568 A1, 2013/0344061 A1,and 2013/0267521 A1. In an exemplary embodiment, the PI3K inhibitor is acompound of Formula (I):

-   or a pharmaceutically acceptable salt thereof,-   wherein:-   Cy is aryl or heteroaryl substituted by 0 or 1 occurrences of R³ and    0, 1, 2, or 3 occurrences of R⁵;-   W_(b) ⁵ is CR⁸, CHR⁸, or N;-   R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,    alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano,    hydroxyl or nitro;-   B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl,    aryl, or heteroaryl, each of which is substituted with 0, 1, 2, 3,    or 4 occurrences of R²;-   each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,    cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,    heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy,    alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro,    phosphate, urea, or carbonate;-   X is —(CH(R⁹))_(z)—;-   Y is —N(R⁹)—C(═O)—, —C(═O)—N(R⁹)—, —C(═O)—N(R⁹)—(CHR⁹)—,    —N(R⁹)—S(═O)—, —S(═O)—N(R⁹)—, S(═O)₂—N(R⁹)—, —N(R⁹)—C(═O)—N(R⁹) or    —N(R⁹)S(═O)₂—;-   z is an integer of 1, 2, 3, or 4;-   R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,    fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy,    sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo, cyano,    aryl, heteroaryl, hydroxyl, or nitro;-   each R⁵ is independently alkyl, alkenyl, alkynyl, cycloalkyl,    heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,    cyano, hydroxyl, or nitro;-   each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl,    or heteroalkyl; or two adjacent occurrences of R⁹ together with the    atoms to which they are attached form a 4- to 7-membered ring;-   W_(d) is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of    which is substituted with one or more R¹⁰, R¹¹, R¹² or R³, and-   R¹⁰, R¹¹, R¹² and R¹³ are each independently hydrogen, alkyl,    heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,    arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy,    amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,    cyano, hydroxyl, nitro, phosphate, urea, carbonate or NR′R″ wherein    R′ and R″ are taken together with nitrogen to form a cyclic moiety.

In an exemplary embodiment, the PI3K inhibitor, PI3K-γ inhibitor, PI3K-δinhibitor, or PI3K-γ,δ inhibitor is a compound of Formula (I-1):

-   or a pharmaceutically acceptable salt thereof,-   wherein:-   B is a moiety of Formula (II):

-   W_(c) is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;-   q is an integer of 0, 1, 2, 3, or 4;-   X is a bond or —(CH(R⁹))_(z)—, and z is an integer of 1, 2, 3 or 4;-   Y is a bond, —N(R⁹)—, —O—, —S—, —S(═O)—, —S(═O)₂, —C(═O)—,    —C(═O)(CHR⁹)_(z)—, —N(R⁹)—C(═O)—, —N(R⁹)—C(═O)NH— or —N(R⁹)C(R⁹)₂—;-   z is an integer of 1, 2, 3, or 4;-   W_(d) is:

-   X₁, X₂ and X₃ are each independently C, CR¹³ or N; and X₄, X₅ and X₆    are each independently N, NH, CR¹³, S or O;-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amido,    alkoxycarbonyl, sulfonamido, halo, cyano, or nitro;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy or    nitro; R.sup.3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,    heterocycloalkyl, alkoxy, amido, amino, alkoxycarbonyl sulfonamido,    halo, cyano, hydroxy or nitro; and-   each instance of R⁹ is independently hydrogen, alkyl, or    heterocycloalkyl.

In an exemplary embodiment, the PI3K inhibitor is a compound of Formula(III), also known as(S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one,

-   or a pharmaceutically acceptable salt thereof.

In an exemplary embodiment, the PI3K inhibitor is a compound of Formula(IV), also known as(S)-3-amino-N-(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)pyrazine-2-carboxamide,

-   or a pharmaceutically acceptable salt thereof.

In an exemplary embodiment, the PI3K inhibitor is a compound selectedfrom the structures disclosed in U.S. Pat. Nos. 8,193,199 and 8,586,739.In an exemplary embodiment, the PI3K inhibitor is a compound of Formula(V):

-   or a pharmaceutically-acceptable salt thereof, wherein:-   X¹ is C(R⁹) or N;-   X² is C(R₁₀) or N;-   Y is N(R¹¹), O or S;-   Z is CR⁸ or N;-   n is 0, 1, 2 or 3;-   R¹ is a direct-bonded or oxygen-linked saturated, partially    saturated or unsaturated 5-, 6- or 7-membered monocyclic ring    containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but    containing no more than one O or S, wherein the available carbon    atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,    wherein the ring is substituted by 0 or 1 R² substituents, and the    ring is additionally substituted by 0, 1, 2 or 3 substituents    independently selected from halo, nitro, cyano, C₁₋₄alkyl,    OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄, N(C₁₋₄alkyl)C₁₋₄alkyl and    C₁₋₄haloalkyl;-   R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),    —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),    —OC(═O)R^(a), —OC(═O)NR^(a)R^(a). —OC(═O)N(R^(a))S(═O)₂R^(a),    —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), OS(═O)R^(a),    —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆    alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² is selected from    C₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle,    —(C₁₋₃alkyl)heteroaryl, —(C₁₋₃alkyl)heterocycle,    —O(C₁₋₃alkyl)heteroaryl, —O(C₁₋₃alkyl)heterocycle,    —NR^(a)(C₁₋₃alkyl)heteroaryl, —NR^(a)(C₁₋₃alkyl)heterocycle,    —(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyl and —NR^(a)(C₁₋₃alkyl)phenyl    all of which are substituted by 0, 1, 2 or 3 substituents selected    from C₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl;-   R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)R^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),    —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R²,    —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),    —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)NR^(a)R^(a),    —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl and    heterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl and    heterocycle are additionally substituted by 0, 1, 2 or 3    substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F, I    and C₁₋₆alkyl;-   R⁴ is, independently, in each instance, halo, nitro, cyano,    C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,    N(C₁₋₄alkyl)C₁₋₄alkyl or C₁₋₄haloalkyl;-   R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,    C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituents    selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,    OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵    groups together form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or 3    substituents selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl,    C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl;-   R⁶ is selected from H, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁷ is selected from H, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁸ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a),    —NR^(a)R^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle,    wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle    are additionally substituted by 0, 1, 2 or 3 substituents selected    from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;-   R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a)C(═NR^(a))NR^(a)R^(a),    —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),    —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(O)NR^(a)R^(a)N(R^(a)C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆    alkylNR^(a)R^(a), —NR^(a)C₁₋₆alkyl, phenyl, benzyl, heteroaryl and    heterocycle, wherein the C₁₋₆ alkyl, phenyl, benzyl, heteroaryl and    heterocycle are additionally substituted by 0, 1, 2 or 3    substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),    —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)C₂₋₆alkylOR^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is a    saturated, partially-saturated or unsaturated 5-, 6- or 7-membered    monocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O    and S, but containing no more than one O or S, wherein the available    carbon atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo    groups, wherein the ring is substituted by 0, 1, 2, 3 or 4    substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),    —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);-   R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a),    C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —S(═O)R^(b), S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);-   R¹¹ is H or C₁₋₄alkyl;-   R^(a) is independently, at each instance, H or R^(b); and-   R^(b) is independently, at each instance, phenyl, benzyl or    C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆ alkyl being substituted by 0,    1, 2 or 3 substituents selected from halo, C₁₋₄alkyl, C₁₋₃    haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

In a preferred embodiment, X¹ is C(R⁹). In a further preferredembodiment, X¹ is C(R⁹) and X² is N. In a further embodiment, X¹ isC(R⁹) and X² is C(R¹⁰).

In a preferred embodiment, R¹ is phenyl substituted by 0 or 1 R²substituents, and the phenyl is additionally substituted by 0, 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl. In one specific embodiment, R¹ is unsubstituted phenyl.In a further specific embodiment, R¹ is phenyl substituted by 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl.

In one specific embodiment, R¹ is selected from 2-methylphenyl,2-chlorophenyl, 2-trifluoromethylphenyl, 2-fluorophenyl and2-methoxyphenyl.

In a further preferred embodiment, R¹ is phenoxy.

In a further preferred embodiment, R¹ is a direct-bonded oroxygen-linked saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic ring containing 1, 2, 3 or 4 atoms selected fromN, O and S, but containing no more than one O or S, wherein theavailable carbon atoms of the ring are substituted by 0, 1 or 2 oxo orthioxo groups, wherein the ring is substituted by 0 or 1 R²substituents, and the ring is additionally substituted by 0, 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl.

In one specific embodiment, R¹ is an unsaturated 5- or 6-memberedmonocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O and S,but containing no more than one O or S, wherein the ring is substitutedby 0 or 1 R² substituents, and the ring is additionally substituted by0, 1, 2 or 3 substituents independently selected from halo, nitro,cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In a further specific embodiment, R¹ is an unsaturated 5- or 6-memberedmonocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O and S,but containing no more than one O or S, wherein the ring is substitutedby 1, 2 or 3 substituents independently selected from halo, nitro,cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In one specific embodiment, R¹ is an unsubstituted unsaturated 5- or6-membered monocyclic ring containing 1, 2, 3 or 4 atoms selected fromN, O and S.

In a further specific embodiment, R¹ is selected from pyridyl andpyrimidinyl.

In one embodiment, R³ is selected from halo, C₁₋₄haloalkyl, cyano,nitro, —C(O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl.

In one preferred embodiment, R³ is H.

In another preferred embodiment, R³ is selected from F, Cl, C₁₋₆alkyl,phenyl, benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl,phenyl, benzyl, heteroaryl and heterocycle are additionally substitutedby 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl,Br, Cl, F, I and C₁₋₆alkyl.

In one embodiment, R⁵ is, independently, in each instance, H, halo,C₁₋₆alkyl, C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3substituents selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl,C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; orboth R⁵ groups together form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or3 substituents selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl,C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl.

In one preferred embodiment, R⁵ is H.

In another preferred embodiment, one R⁵ is S-methyl, the other is H.

In another preferred embodiment, at least one R⁵ is halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl.

In a preferred embodiment, R⁶ is H.

In another preferred embodiment, R⁶ is F, Cl, cyano or nitro.

In a preferred embodiment, R⁷ is H.

In another preferred embodiment, R⁷ is F, Cl, cyano or nitro.

In a preferred embodiment, R⁸ is selected from H, CF₃, C₁₋₃alkyl, Br, Cland F.

In one specific embodiment, R⁸ is H.

In another specific embodiment, R⁸ is selected from CF₃, C₁₋₃alkyl, Br,Cl and F.

In a preferred embodiment, R⁹ is H.

In another embodiment, R⁹ is selected from halo, C₁₋₄haloalkyl, cyano,nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),N(R^(a))C(═NR^(a))NR^(a)R^(a), N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a).

In one embodiment, R⁹ is a saturated, partially-saturated or unsaturated5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atomsselected from N, O and S, but containing no more than one O or S,wherein the available carbon atoms of the ring are substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2, 3or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR, —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In one preferred embodiment, R¹⁰ is H.

In another preferred embodiment, R¹⁰ is cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a).

In one preferred embodiment, R¹¹ is H.

In another exemplary embodiment, the PI3K inhibitor is a compound ofFormula (VI):

-   or a pharmaceutically-acceptable salt thereof, wherein:-   X¹ is C(R⁹) or N;-   X² is C(R¹⁰) or N;-   Y is N(R¹¹), O or S;-   Z is CR⁸ or N;-   R¹ is a direct-bonded or oxygen-linked saturated,    partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic    ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but    containing no more than one O or S, wherein the available carbon    atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,    wherein the ring is substituted by 0 or 1 R² substituents, and the    ring is additionally substituted by 0, 1, 2 or 3 substituents    independently selected from halo, nitro, cyano, C₁₋₄alkyl,    OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄ alkyl)C₁₋₄alkyl and    C₁₋₄haloalkyl;-   R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),    —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),    —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),    —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —S(═O)R^(a),    —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆    alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² is selected from    C₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle,    —(C₁₋₃alkyl)heteroaryl, —(C₁₋₃alkyl)heterocycle,    —O(C₁₋₃alkyl)heteroaryl, —O(C₁₋₃alkyl)heterocycle,    —NR^(a)(C₁₋₃alkyl)heteroaryl, —NR^(a)(C₁₋₃alkyl)heterocycle,    —(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyl and —NR^(a)(C₁₋₃alkyl)phenyl    all of which are substituted by 0, 1, 2 or 3 substituents selected    from C₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl;-   R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a)C(═NR^(a))NR^(a)R^(a),    —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),    —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),    N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl and    heterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl and    heterocycle are additionally substituted by 0, 1, 2 or 3    substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F, I    and C₁₋₆alkyl;-   R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,    C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituents    selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,    OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵    groups together form a C₃₋₆-spiroalkyl substituted by 0, 1, 2 or 3    substituents selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl,    C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl;-   R⁶ is selected from H, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁷ is selected from H, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)RaS(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),    —S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),    —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁸ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a),    —NR^(a)R^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle,    wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle    are additionally substituted by 0, 1, 2 or 3 substituents selected    from C₁₋₆haloalkyl, OC₁₋₆ alkyl, Br, Cl, F, I and C₁₋₆alkyl;-   R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),    —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl,    phenyl, benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl,    phenyl, benzyl, heteroaryl and heterocycle are additionally    substituted by 0, 1, 2 or 3 substituents selected from halo,    C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),    —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR, —OC(═O)R^(a),    —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylOR^(a),    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),    —S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),    —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),    —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),    N(R^(a))C(═NR^(a))NR^(a)R^(a), N(R^(a))S(═O)₂R^(a),    N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a),    —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is a saturated, partially-saturated or    unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2,    3 or 4 atoms selected from N, O and S, but containing no more than    one O or S, wherein the available carbon atoms of the ring are    substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring is    substituted by 0, 1, 2, 3 or 4 substituents selected from halo,    C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),    —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),    —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylOR^(a),    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),    —S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),    —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),    —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),    N(R^(a))C(═NR^(a))NR^(a)R^(a), N(R^(a))S(═O)₂R^(a),    —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆ alkylNR^(a)R^(a) and    —NR^(a)C₂₋₆alkylOR^(a);-   R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a),    C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —S(═O)R^(b), S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a); —R¹¹ is H or    C₁₋₄alkyl;-   R^(a) is independently, at each instance, H or R^(b); and-   R^(b) is independently, at each instance, phenyl, benzyl or    C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆ alkyl being substituted by 0,    1, 2 or 3 substituents selected from halo, C₁₋₄alkyl, C₁₋₃    haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

In a preferred embodiment, X¹ is C(R⁹). In a further preferredembodiment, X¹ is C(R⁹) and X² is N. In a further embodiment, X¹ isC(R⁹) and X² is C(R¹⁰).

In a preferred embodiment, R¹ is phenyl substituted by 0 or 1 R²substituents, and the phenyl is additionally substituted by 0, 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl. In one specific embodiment, R¹ is unsubstituted phenyl.In a further specific embodiment, R¹ is phenyl substituted by 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl.

In one specific embodiment, R¹ is selected from 2-methylphenyl,2-chlorophenyl, 2-trifluoromethylphenyl, 2-fluorophenyl and2-methoxyphenyl.

In a further preferred embodiment, R¹ is phenoxy.

In a further preferred embodiment, R¹ is a direct-bonded oroxygen-linked saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic ring containing 1, 2, 3 or 4 atoms selected fromN, O and S, but containing no more than one O or S, wherein theavailable carbon atoms of the ring are substituted by 0, 1 or 2 oxo orthioxo groups, wherein the ring is substituted by 0 or 1 R²substituents, and the ring is additionally substituted by 0, 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl.

In one specific embodiment, R¹ is an unsaturated 5- or 6-memberedmonocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O and S,but containing no more than one O or S, wherein the ring is substitutedby 0 or 1 R² substituents, and the ring is additionally substituted by0, 1, 2 or 3 substituents independently selected from halo, nitro,cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In a further specific embodiment, R¹ is an unsaturated 5- or 6-memberedmonocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O and S,but containing no more than one O or S, wherein the ring is substitutedby 1, 2 or 3 substituents independently selected from halo, nitro,cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In one specific embodiment, R¹ is an unsubstituted unsaturated 5- or6-membered monocyclic ring containing 1, 2, 3 or 4 atoms selected fromN, O and S.

In a further specific embodiment, R¹ is selected from pyridyl andpyrimidinyl.

In one embodiment, R³ is selected from halo, C₁₋₄haloalkyl, cyano,nitro, —C(O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl.

In one preferred embodiment, R³ is H.

In another preferred embodiment, R³ is selected from F, Cl, C₁₋₆alkyl,phenyl, benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl,phenyl, benzyl, heteroaryl and heterocycle are additionally substitutedby 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl,Br, Cl, F, I and C₁₋₆alkyl.

In one embodiment, R⁵ is, independently, in each instance, H, halo,C₁₋₆alkyl, C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3substituents selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl,C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; orboth R⁵ groups together form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or3 substituents selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl,C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl.

In one preferred embodiment, R⁵ is H.

In another preferred embodiment, one R⁵ is S-methyl, the other is H.

In another preferred embodiment, at least one R⁵ is halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl.

In a preferred embodiment, R⁶ is H.

In another preferred embodiment, R⁶ is F, Cl, cyano or nitro.

In a preferred embodiment, R⁷ is H.

In another preferred embodiment, R⁷ is F, Cl, cyano or nitro.

In a preferred embodiment, R⁸ is selected from H, CF₃, C₁₋₃alkyl, Br, Cland F.

In one specific embodiment, R⁸ is H.

In another specific embodiment, R⁸ is selected from CF₃, C₁₋₃alkyl, Br,Cl and F.

In a preferred embodiment, R⁹ is H.

In another embodiment, R⁹ is selected from halo, C₁₋₄haloalkyl, cyano,nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a).

In one embodiment, R⁹ is a saturated, partially-saturated or unsaturated5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atomsselected from N, O and S, but containing no more than one O or S,wherein the available carbon atoms of the ring are substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2, 3or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In one preferred embodiment, R¹⁰ is H.

In another preferred embodiment, R¹⁰ is cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a).

In one preferred embodiment, R¹¹ is H.

In another exemplary embodiment, the PI3K inhibitor is a compound ofFormula (VII):

-   or a pharmaceutically-acceptable salt thereof, wherein:-   X¹ is C(R⁹) or N;-   X² is C(R¹⁰) or N;-   Y is N(R¹¹), O or S;-   Z is CR⁸ or N; R¹ is a direct-bonded or oxygen-linked saturated,    partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic    ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but    containing no more than one O or S, wherein the available carbon    atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,    wherein the ring is substituted by 0 or 1 R² substituents, and the    ring is additionally substituted by 0, 1, 2 or 3 substituents    independently selected from halo, nitro, cyano, C₁₋₄alkyl,    OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl and    C₁₋₄haloalkyl;-   R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),    —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),    —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),    —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),    —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆    alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² is selected from    C₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle,    —(C₁₋₃alkyl)heteroaryl, —(C₁₋₃alkyl)heterocycle,    —O(C₁₋₃alkyl)heteroaryl, —O(C₁₋₃alkyl)heterocycle,    —NR^(a)(C₁₋₃alkyl)heteroaryl, —NR^(a)(C₁₋₃alkyl)heterocycle,    —(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyl and —NR^(a)(C₁₋₃alkyl)phenyl    all of which are substituted by 0, 1, 2 or 3 substituents selected    from C₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl;-   R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),    —S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),    —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),    —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),    —N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),    —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a),    —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl and    heterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl and    heterocycle are additionally substituted by 0, 1, 2 or 3    substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F, I    and C₁₋₆alkyl;-   R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,    C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituents    selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,    OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵    groups together form a C₃₋₆-spiroalkyl substituted by 0, 1, 2 or 3    substituents selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl,    C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl;-   R⁶ is selected from H, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)RaS(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),    —S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),    —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁷ is selected from H, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)RaS(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),    —S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),    —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁸ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a),    —NR^(a)R^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle,    wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle    are additionally substituted by 0, 1, 2 or 3 substituents selected    from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;-   R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR, —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),    —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),    N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl and    heterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl and    heterocycle are additionally substituted by 0, 1, 2 or 3    substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR⁸, —OC(═O)R⁸, —OC(═O)NR²R⁸,    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),    —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R,    S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),    N(R^(a))S(═O)₂R^(a), N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is a    saturated, partially-saturated or unsaturated 5-, 6- or 7-membered    monocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O    and S, but containing no more than one O or S, wherein the available    carbon atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo    groups, wherein the ring is substituted by 0, 1, 2, 3 or 4    substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),    —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);-   R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a),    C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —S(═O)R^(b), S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);-   R¹¹ is H or C₁₋₄alkyl;-   R^(a) is independently, at each instance, H or R^(b); and-   R^(b) is independently, at each instance, phenyl, benzyl or    C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl being substituted by 0,    1, 2 or 3 substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl,    —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

In a preferred embodiment, X¹ is C(R⁹). In a further preferredembodiment, X¹ is C(R⁹) and X² is N. In a further embodiment, X¹ isC(R⁹) and X² is C(R¹⁰).

In a preferred embodiment, R¹ is phenyl substituted by 0 or 1 R²substituents, and the phenyl is additionally substituted by 0, 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl. In one specific embodiment, R¹ is unsubstituted phenyl.In a further specific embodiment, R¹ is phenyl substituted by 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl.

In one specific embodiment, R¹ is selected from 2-methylphenyl,2-chlorophenyl, 2-trifluoromethylphenyl, 2-fluorophenyl and2-methoxyphenyl.

In a further preferred embodiment, R¹ is phenoxy.

In a further preferred embodiment, R¹ is a direct-bonded oroxygen-linked saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic ring containing 1, 2, 3 or 4 atoms selected fromN, O and S, but containing no more than one O or S, wherein theavailable carbon atoms of the ring are substituted by 0, 1 or 2 oxo orthioxo groups, wherein the ring is substituted by 0 or 1 R²substituents, and the ring is additionally substituted by 0, 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl.

In one specific embodiment, R¹ is an unsaturated 5- or 6-memberedmonocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O and S,but containing no more than one O or S, wherein the ring is substitutedby 0 or 1 R² substituents, and the ring is additionally substituted by0, 1, 2 or 3 substituents independently selected from halo, nitro,cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In a further specific embodiment, R¹ is an unsaturated 5- or 6-memberedmonocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O and S,but containing no more than one O or S, wherein the ring is substitutedby 1, 2 or 3 substituents independently selected from halo, nitro,cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In one specific embodiment, R¹ is an unsubstituted unsaturated 5- or6-membered monocyclic ring containing 1, 2, 3 or 4 atoms selected fromN, O and S.

In a further specific embodiment, R¹ is selected from pyridyl andpyrimidinyl.

In one embodiment, R³ is selected from halo, C₁₋₄haloalkyl, cyano,nitro, —C(O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl.

In one preferred embodiment, R³ is H.

In another preferred embodiment, R³ is selected from F, Cl, C₁₋₆alkyl,phenyl, benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl,phenyl, benzyl, heteroaryl and heterocycle are additionally substitutedby 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl,Br, Cl, F, I and C₁₋₆alkyl.

In one embodiment, R⁵ is, independently, in each instance, H, halo,C₁₋₆alkyl, C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3substituents selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl,C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; orboth R⁵ groups together form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or3 substituents selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl,C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl.

In one preferred embodiment, R⁵ is H.

In another preferred embodiment, one R⁵ is S-methyl, the other is H.

In another preferred embodiment, at least one R⁵ is halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl.

In a preferred embodiment, R⁶ is H.

In another preferred embodiment, R⁶ is F, Cl, cyano or nitro.

In a preferred embodiment, R⁷ is H.

In another preferred embodiment, R⁷ is F, Cl, cyano or nitro.

In a preferred embodiment, R⁸ is selected from H, CF₃, C₁₋₃alkyl, Br, Cland F.

In one specific embodiment, R⁸ is H.

In another specific embodiment, R⁸ is selected from CF₃, C₁₋₃alkyl, Br,Cl and F.

In a preferred embodiment, R⁹ is H.

In another embodiment, R⁹ is selected from halo, C₁₋₄haloalkyl, cyano,nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), N(R^(a))S(═O)₂R^(a),N(R^(a))S(═O)₂NR^(a)R^(a), NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),——N(R^(a))S(═O)₂R^(a), N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a).

In one embodiment, R⁹ is a saturated, partially-saturated or unsaturated5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atomsselected from N, O and S, but containing no more than one O or S,wherein the available carbon atoms of the ring are substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2, 3or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR, —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In one preferred embodiment, R¹⁰ is H.

In another preferred embodiment, R¹⁰ is cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a).

In one preferred embodiment, R¹¹ is H.

In another exemplary embodiment, the PI3K inhibitor is a compound ofFormula (VIII):

-   or a pharmaceutically-acceptable salt thereof, wherein:-   X¹ is C(R⁹) or N;-   X² is C(R¹⁰) or N;-   Y is N(R¹¹), O or S;-   Z is CR⁸ or N;-   R¹ is a direct-bonded or oxygen-linked saturated,    partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic    ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but    containing no more than one O or S, wherein the available carbon    atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,    wherein the ring is substituted by 0 or 1 R² substituents, and the    ring is additionally substituted by 0, 1, 2 or 3 substituents    independently selected from halo, nitro, cyano, C₁₋₄alkyl,    OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄ alkyl)C₁₋₄alkyl and    C₁₋₄haloalkyl;-   R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),    —C(═O)OR^(a), —C(═O)NR^(a)R^(a)—C(═NR^(a))NR^(a)R^(a), —OR^(a),    —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),    —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆    alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² is selected from    C₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle,    —(C₁₋₃alkyl)heteroaryl, —(C₁₋₃alkyl)heterocycle, —O(C₁₋₃    alkyl)heteroaryl, —O(C₁₋₃alkyl)heterocycle,    —NR^(a)(C₁₋₃alkyl)heteroaryl, —NR^(a)(C₁₋₃ alkyl)heterocycle,    —(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyl and —NR^(a)(C₁₋₃alkyl)phenyl    all of which are substituted by 0, 1, 2 or 3 substituents selected    from C₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl;-   R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a) C(═NR^(a))NR^(a)R^(a),    —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),    —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)NR^(a), —NR^(a),    —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl and    heterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl and    heterocycle are additionally substituted by 0, 1, 2 or 3    substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F, I    and C₁₋₆alkyl;-   R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,    C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituents    selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,    OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵    groups together form a C₃₋₆-spiroalkyl substituted by 0, 1, 2 or 3    substituents selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl,    C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl;-   R⁶ is selected from H, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁷ is selected from H, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁸ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a),    —NR^(a)R^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle,    wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle    are additionally substituted by 0, 1, 2 or 3 substituents selected    from C₁₋₆haloalkyl, OC₁₋₆ alkyl, Br, Cl, F, I and C₁₋₆alkyl;-   R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR, —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),    —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl,    phenyl, benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl,    phenyl, benzyl, heteroaryl and heterocycle are additionally    substituted by 0, 1, 2 or 3 substituents selected from halo,    C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),    —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),    —OC(═O)R^(a)OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),    —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is a    saturated, partially-saturated or unsaturated 5-, 6- or 7-membered    monocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O    and S, but containing no more than one O or S, wherein the available    carbon atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo    groups, wherein the ring is substituted by 0, 1, 2, 3 or 4    substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,    —C(O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),    —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),    —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆    alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);-   R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a),    C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —S(═O)R^(b), S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);-   R¹¹ is H or C₁₋₄alkyl;-   R^(a) is independently, at each instance, H or R^(b); and-   R^(b) is independently, at each instance, phenyl, benzyl or    C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆ alkyl being substituted by 0,    1, 2 or 3 substituents selected from halo, C₁₋₄alkyl, C₁₋₃    haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

In a preferred embodiment, X¹ is C(R⁹). In a further preferredembodiment, X¹ is C(R⁹) and X² is N. In a further embodiment, X¹ isC(R⁹) and X² is C(R¹⁰).

In a preferred embodiment, R¹ is phenyl substituted by 0 or 1 R²substituents, and the phenyl is additionally substituted by 0, 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl. In one specific embodiment, R¹ is unsubstituted phenyl.In a further specific embodiment, R¹ is phenyl substituted by 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl.

In one specific embodiment, R¹ is selected from 2-methylphenyl,2-chlorophenyl, 2-trifluoromethylphenyl, 2-fluorophenyl and2-methoxyphenyl.

In a further preferred embodiment, R¹ is phenoxy.

In a further preferred embodiment, R¹ is a direct-bonded oroxygen-linked saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic ring containing 1, 2, 3 or 4 atoms selected fromN, O and S, but containing no more than one O or S, wherein theavailable carbon atoms of the ring are substituted by 0, 1 or 2 oxo orthioxo groups, wherein the ring is substituted by 0 or 1 R²substituents, and the ring is additionally substituted by 0, 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl.

In one specific embodiment, R¹ is an unsaturated 5- or 6-memberedmonocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O and S,but containing no more than one O or S, wherein the ring is substitutedby 0 or 1 R² substituents, and the ring is additionally substituted by0, 1, 2 or 3 substituents independently selected from halo, nitro,cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In a further specific embodiment, R¹ is an unsaturated 5- or 6-memberedmonocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O and S,but containing no more than one O or S, wherein the ring is substitutedby 1, 2 or 3 substituents independently selected from halo, nitro,cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In one specific embodiment, R¹ is an unsubstituted unsaturated 5- or6-membered monocyclic ring containing 1, 2, 3 or 4 atoms selected fromN, O and S.

In a further specific embodiment, R¹ is selected from pyridyl andpyrimidinyl.

In one embodiment, R³ is selected from halo, C₁₋₄haloalkyl, cyano,nitro, —C(O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl.

In one preferred embodiment, R³ is H.

In another preferred embodiment, R³ is selected from F, Cl, C₁₋₆alkyl,phenyl, benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl,phenyl, benzyl, heteroaryl and heterocycle are additionally substitutedby 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl,Br, Cl, F, I and C₁₋₆alkyl.

In one embodiment, R⁵ is, independently, in each instance, H, halo,C₁₋₆alkyl, C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3substituents selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl,C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; orboth R⁵ groups together form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or3 substituents selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl,C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl.

In one preferred embodiment, R⁵ is H.

In another preferred embodiment, one R⁵ is S-methyl, the other is H.

In another preferred embodiment, at least one R⁵ is halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl.

In a preferred embodiment, R⁶ is H.

In another preferred embodiment, R⁶ is F, Cl, cyano or nitro.

In a preferred embodiment, R⁷ is H.

In another preferred embodiment, R⁷ is F, Cl, cyano or nitro.

In a preferred embodiment, R⁸ is selected from H, CF₃, C₁₋₃alkyl, Br, Cland F.

In one specific embodiment, R⁸ is H.

In another specific embodiment, R⁸ is selected from CF₃, C₁₋₃alkyl, Br,Cl and F.

In a preferred embodiment, R⁹ is H.

In another embodiment, R⁹ is selected from halo, C₁₋₄haloalkyl, cyano,nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a).

In one embodiment, R⁹ is a saturated, partially-saturated or unsaturated5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atomsselected from N, O and S, but containing no more than one O or S,wherein the available carbon atoms of the ring are substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2, 3or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR, —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In one preferred embodiment, R¹⁰ is H.

In another preferred embodiment, R¹⁰ is cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a).

In one preferred embodiment, R¹¹ is H.

In an exemplary preferred embodiment, the PI3K inhibitor is a compoundof Formula (IX):

which is(S)—N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine,or a pharmaceutically-acceptable salt thereof. In an exemplaryembodiment, the PI3K-δ inhibitor or PI3K-δ inhibitor is(S)—N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amineor a pharmaceutically-acceptable salt thereof.

In an exemplary embodiment, the PI3K inhibitor is a PI3K-δ inhibitorwhich is a compound of Formula (X):

which is(S)—N-(1-(6-fluoro-3-(pyridin-2-yl)quinoxalin-2-yl)ethyl)-9H-purin-6-amine,or a pharmaceutically-acceptable salt thereof.

In an exemplary embodiment, the PI3K inhibitor is a PI3K-δ inhibitor,which is a compound of Formula (XI):

which is(S)—N-(1-(2-(3,5-difluorophenyl)-8-fluoroquinolin-3-yl)ethyl)-9H-purin-6-amine,or a pharmaceutically-acceptable salt thereof.

In an exemplary embodiment, the PI3K inhibitor or PI3K-δ inhibitor is(S)—N-(1-(2-(3,5-difluorophenyl)-8-fluoroquinolin-3-yl)ethyl)-9H-purin-6-amineor a pharmaceutically-acceptable salt thereof.

In an exemplary embodiment, the PI3K inhibitor is a PI3K-δ inhibitorwhich is a compound of Formula (XII):

which is(S)-3-(1-((9H-purin-6-yl)amino)ethyl)-2-(pyridin-2-yl)quinoline-8-carbonitrile,or a pharmaceutically-acceptable salt thereof

In an exemplary embodiment, the PI3K inhibitor or PI3K-δ inhibitor is(S)-3-(1-((9H-purin-6-yl)amino)ethyl)-2-(pyridin-2-yl)quinoline-8-carbonitrileor a pharmaceutically-acceptable salt thereof.

In an exemplary embodiment, the PI3K inhibitor is a PI3K-δ inhibitorwhich is a compound of Formula (XIII):

which is(S)—N-(1-(5,7-difluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine,or a pharmaceutically-acceptable salt thereof

In an exemplary embodiment, the PI3K inhibitor or PI3K-δ inhibitor is(S)—N-(1-(5,7-difluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amineor a pharmaceutically-acceptable salt thereof.

In an exemplary embodiment, the PI3K inhibitor is a compound selectedfrom the structures disclosed in U.S. Pat. Nos. 7,932,260 and 8,207,153.In an exemplary embodiment, the PI3K inhibitor is a compound of Formula(XIV):

-   wherein-   X and Y, independently, are N or CH;-   Z is N—R⁷ or O;-   R¹ are the same and are hydrogen, halo, or C₁₋₃alkyl;-   R² and R³, independently, are hydrogen, halo, or C₁₋₃alkyl;-   R⁴ is hydrogen, halo, OR^(a), CN, C₂₋₆alkynyl, C(═O)R^(a),    C(═O)NR^(a)R^(b), C₃₋₆heterocycloalkyl, C₁₋₃    alkyleneC₃₋₆heterocycloalkyl, OC₁₋₃alkyleneOR^(a),    OC₁₋₃alkyleneNR^(a)R^(b), OC₁₋₃alkyleneC₃₋₆ cycloalkyl,    OC₃₋₆heterocycloalkyl, OC₁₋₃alkyleneC≡CH, or    OC₁₋₃alkyleneC(═O)NR^(a)R^(b);-   R⁵ is C₁₋₃alkyl, CH₂CF₃, phenyl, CH₂C≡CH, C₁₋₃alkyleneOR^(e),    C₁₋₄alkyleneNR^(a)R^(b), or C₁₋₄ alkyleneNHC(═O)OR^(a),-   R⁶ is hydrogen, halo, or NR^(a)R^(b);-   R⁷ is hydrogen or R⁵ and R⁷ are taken together with the atoms to    which they are attached to form a five- or six-membered saturated    ring;-   R⁸ is C₁₋₃alkyl, halo, CF₃, or CH₂C₃₋₆heterocycloalkyl;-   n is 0, 1, or 2;-   R^(a) is hydrogen, C₁₋₄alkyl, or CH₂C₆H₅;-   R^(b) is hydrogen or C₁₋₃alkyl; and-   R^(c) is hydrogen, C₁₋₃alkyl, or halo,-   wherein when the R¹ groups are different from hydrogen, R² and R⁴    are the same; or a pharmaceutically acceptable salt, or prodrug, or    solvate (e.g., hydrate) thereof.

In a preferred embodiment, the PI3K inhibitor is an enantiomer ofFormula (XIV), as shown in Formula (XV):

wherein X, Y, Z, R¹ through R⁸, R^(a), R^(b), Rfc, and n are as definedabove for Formula (XIV).

In various embodiments exhibiting increased potency relative to othercompounds, R⁸ is C₁₋₃alkyl, F, Cl, or CF₃. Alternatively, in suchembodiments, n is 0 (such that there is no R⁸ substituent).

In further embodiments exhibiting increased potency, X is N and Y is CH.Alternatively, X and Y may also both be CH.

In preferred embodiments, Z is N—R⁷, and the bicyclic ring systemcontaining X and Y is:

In further embodiments exhibiting increased potency, R⁶ is hydrogen,halo, or NH₂. Preferably, R⁶ is hydrogen.

In preferred embodiments exhibiting such increased potency, n is 0 or 1;R⁸ (if n is 1) is C₁₋₃alkyl, F, Cl, or CF₃; R⁶ is hydrogen; X is N and Yis CH or X and Y are both CH; Z is NH; R¹ are the same and are hydrogen,halo, or C₁₋₃alkyl; and R² and R³, independently, are hydrogen, halo, orC₁₋₃alkyl. Preferably, R¹, R², and R³ are hydrogen.

Unexpectedly, potency against PI3K-δ is conserved when R¹ is the same.In structural formulae (XIV) and (XV), R² and R⁴ may differ providedthat R¹ is H. When R¹ is H, free rotation is unexpectedly permittedabout the bond connecting the phenyl ring substituent to the quinazolinering, and the compounds advantageously do not exhibit atropisomerism(i.e., multiple diastereomer formation is avoided). Alternatively, R²and R⁴ can be the same such that the compounds advantageously do notexhibit atropisomerism.

As used with respect to Formula (XIV) and Formula (XV), the term “alkyl”is defined as straight chained and branched hydrocarbon groupscontaining the indicated number of carbon atoms, e.g., methyl, ethyl,and straight chain and branched propyl and butyl groups. The terms“C₁₋₃alkylene” and “C₁₋₄alkylene” are defined as hydrocarbon groupscontaining the indicated number of carbon atoms and one less hydrogenthan the corresponding alkyl group. The term “C₂₋₆alkynyl” is defined asa hydrocarbon group containing the indicated number of carbon atoms anda carbon-carbon triple bond. The term “C₃₋₆cycloalkyl” is defined as acyclic hydrocarbon group containing the indicated number of carbonatoms. The term “C₂₋₆heterocycloalkyl” is defined similarly ascycloalkyl except the ring contains one or two heteroatoms selected fromthe group consisting of O, NR^(a), and S. The term “halo” is defined asfluoro, bromo, chloro, and iodo.

In other preferred embodiments, R¹ is hydrogen, fluoro, chloro, methyl,or

and R² is hydrogen, methyl, chloro, or fluoro; R³ is hydrogen or fluoro;R⁶ is NH₂, hydrogen, or fluoro; R⁷ is hydrogen or R⁵ and R⁷ are takentogether to form

R⁸ is methyl, trifluoromethyl, chloro, or fluoro; R⁴ is hydrogen,fluoro, chloro, OH, OCH₃, OCH₂C≡CH, O(CH₂)₂N(CH₃)₂, C(═O)CH₃, C≡CH, CN,C(═O)NH₂, OCH₂C(═O)NH₂, O(CH₂)₂OCH₃, O(CH₂)₂N(CH₃)₂,

and R⁵ is methyl, ethyl, propyl, phenyl, CH₂OH, CH₂OCH₂C₆H₅, CH₂CF₃,CH₂OC(CH₃)₃, CH₂C≡CH, (CH₂)₃N(C₂H₅)₂, (CH₂)₃NH₂, (CH₂)₄NH₂,(CH₂)₃NHC(═O)OCH₂C₆H₅, or (CH₂)₄NHC(═O)OCH₂C₆H₅; R^(c) is hydrogen,methyl, fluoro, or bromo; and n is 0 or 1.

In a preferred embodiment, the PI3K inhibitor is a PI3K-δ inhibitor ofFormula (XVI):

which is(S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(other names: 4(3H)-quinazolinone,5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl], and5-fluoro-3-phenyl-2-{(1S)-1-[(7H-purin-6-yl)amino]propyl}quinazolin-4(3H)-one)or a pharmaceutically-acceptable salt thereof.

In a preferred embodiment, the PI3K inhibitor or PI3K-δ inhibitor is(S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneor a pharmaceutically-acceptable salt thereof.

In an embodiment, the PI3K inhibitor or PI3K-δ inhibitor is4(3H)-quinazolinone,5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-5-fluoro-3-phenyl-2-{(1S)-1-[(7H-purin-6-yl)amino]propyl}quinazolin-4(3H)-one or apharmaceutically-acceptable salt thereof

Other PI3K inhibitors suitable for use in the described combination witha BTK inhibitor also include, but are not limited to, those describedin, for example, U.S. Pat. No. 8,193,182 and U.S. Published ApplicationNos. 2013/0267521; 2013/0053362; 2013/0029984; 2013/0029982;2012/0184568; and 2012/0059000.

BTK Inhibitors

The BTK inhibitor may be any BTK inhibitor known in the art. Inparticular, it is one of the BTK inhibitors described in more detail inthe following paragraphs. Preferably, it is a compound of Formula XVIIor a pharmaceutically acceptable salt thereof. In one specificembodiment, it is a compound of Formula XVIII or a pharmaceuticallyacceptable salt thereof.

In an exemplary embodiment, the BTK inhibitor is a compound of Formula(XVII):

-   or a pharmaceutically acceptable salt thereof,-   wherein:-   X is CH, N, O or S;-   Y is C(R₆), N, O or S;-   Z is CH, N or bond;-   A is CH or N;-   B₁ is N or C(R₇);-   B₂ is N or C(R₈);-   B₃ is N or C(R₉);-   B₄ is N or C(R₁₀);-   R₁ is R₁₁C(═O), R₁₂S(═O), R₁₃S(═O)₂ or (1-6C)alkyl optionally    substituted with R₁₄;-   R₂ is H, (C₁₋₃)alkyl or (C₃₋₇)cycloalkyl;-   R₃ is H, (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl); or-   R₂ and R₃ form, together with the N and C atom they are attached to,    a (3-7C)heterocycloalkyl optionally substituted with one or more    fluorine, hydroxyl, (1-3C)alkyl, (1-3C)alkoxy or oxo;-   R₄ is H or (C₁₋₃)alkyl;-   R₅ is H, halogen, cyano, (C₁₋₄)alkyl, (C₁₋₃)alkoxy,    (C₃₋₆)cycloalkyl, any alkyl group of which is optionally substituted    with one or more halogen; or R₅ is (C₆₋₁₀)aryl or    (C₂₋₆)heterocycloalkyl;-   R₆ is H or (C₁₋₃)alkyl; or-   R₅ and R₆ together may form a (C₃₋₇)cycloalkenyl or    (C₂₋₆)heterocycloalkenyl, each optionally substituted with    (C₁₋₃)alkyl or one or more halogens;-   R₇ is H, halogen, CF₃, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;-   R₈ is H, halogen, CF₃, (C₁₋₃)alkyl or (C₁₋₃)alkoxy; or-   R₇ and R₈ together with the carbon atoms they are attached to, form    (C₆₋₁₀)aryl or (C₁₋₉)heteroaryl;-   R₉ is H, halogen, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;-   R₁₀ is H, halogen, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;-   R₁₁ is independently selected from the group consisting of    (C₁₋₆)alkyl, (C₂₋₆)alkenyl and (C₂₋₆)alkynyl, where each alkyl,    alkenyl or alkynyl is optionally substituted with one or more    substituents selected from the group consisting of hydroxyl,    (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl, [(C₁₋₄)alkyl]amino,    di[(C₁₋₄)alkyl]amino, (C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl    and (C₃₋₇)heterocycloalkyl; or R₁₁ is    (C₁₋₃)alkyl-C(O)—S—(C₁₋₃)alkyl; or-   R₁₁ is (C₁₋₅)heteroaryl optionally substituted with one or more    substituents selected from the group consisting of halogen or cyano;-   R₁₂ and R₁₃ are independently selected from the group consisting of    (C₂₋₆)alkenyl or (C₂₋₆)alkynyl, both optionally substituted with one    or more substituents selected from the group consisting of hydroxyl,    (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl, [(C₁₋₄)alkyl]amino,    di[(C₁₋₄)alkyl]amino, (C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl    and (C₃₋₇)heterocycloalkyl; or a (C₁₋₅)heteroaryl optionally    substituted with one or more substituents selected from the group    consisting of halogen and cyano; and-   R₁₄ is independently selected from the group consisting of halogen,    cyano, (C₂₋₆)alkenyl and (C₂₋₆)alkynyl, both optionally substituted    with one or more substituents selected from the group consisting of    hydroxyl, (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₄)alkylamino,    di[(C₁₋₄)alkyl]amino, (C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl,    (C₁₋₅)heteroaryl and (C₃₋₇)heterocycloalkyl;-   with the proviso that:-   0 to 2 atoms of X, Y, Z can simultaneously be a heteroatom;-   when one atom selected from X, Y is O or S, then Z is a bond and the    other atom selected from X, Y can not be O or S;-   when Z is C or N then Y is C(R₆) or N and X is C or N;-   0 to 2 atoms of B₁, B₂, B₃ and B₄ are N;-   with the terms used having the following meanings:-   (C₁₋₂)alkyl means an alkyl group having 1 to 2 carbon atoms, being    methyl or ethyl,-   (C₁₋₃)alkyl means a branched or unbranched alkyl group having 1-3    carbon atoms, being methyl, ethyl, propyl or isopropyl;-   (C₁₋₄)alkyl means a branched or unbranched alkyl group having 1-4    carbon atoms, being methyl, ethyl, propyl, isopropyl, butyl,    isobutyl, sec-butyl and tert-butyl, (C₁₋₃)alkyl groups being    preferred;-   (C₁₋₅)alkyl means a branched or unbranched alkyl group having 1-5    carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl,    isobutyl, sec-butyl, tert-butyl, pentyl and isopentyl, (C₁₋₄)alkyl    groups being preferred. (C₁₋₆)alkyl means a branched or unbranched    alkyl group having 1-6 carbon atoms, for example methyl, ethyl,    propyl, isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl.    (C₁₋₅)alkyl groups are preferred, (C₁₋₄)alkyl being most preferred;-   (C₁₋₂)alkoxy means an alkoxy group having 1-2 carbon atoms, the    alkyl moiety having the same meaning as previously defined;-   (C₁₋₃)alkoxy means an alkoxy group having 1-3 carbon atoms, the    alkyl moiety having the same meaning as previously defined.    (C₁₋₂)alkoxy groups are preferred;-   (C₁₋₄)alkoxy means an alkoxy group having 1-4 carbon atoms, the    alkyl moiety having the same meaning as previously defined.    (C₁₋₃)alkoxy groups are preferred, (C₁₋₂)alkoxy groups being most    preferred;-   (C₂₋₄)alkenyl means a branched or unbranched alkenyl group having    2-4 carbon atoms, such as ethenyl, 2-propenyl, isobutenyl or    2-butenyl;-   (C₂₋₆)alkenyl means a branched or unbranched alkenyl group having    2-6 carbon atoms, such as ethenyl, 2-butenyl, and n-pentenyl,    (C₂₋₄)alkenyl groups being most preferred;-   (C₂₋₄)alkynyl means a branched or unbranched alkynyl group having    2-4 carbon atoms, such as ethynyl, 2-propynyl or 2-butynyl;-   (C₂₋₆)alkynyl means a branched or unbranched alkynyl group having    2-6 carbon atoms, such as ethynyl, propynyl, n-butynyl, n-pentynyl,    isopentynyl, isohexynyl or n-hexynyl. (C₂₋₄)alkynyl groups are    preferred; (C₃₋₆)cycloalkyl means a cycloalkyl group having 3-6    carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl or    cyclohexyl;-   (C₃₋₇)cycloalkyl means a cycloalkyl group having 3-7 carbon atoms,    being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or    cycloheptyl;-   (C₂₋₆)heterocycloalkyl means a heterocycloalkyl group having 2-6    carbon atoms, preferably 3-5 carbon atoms, and one or two    heteroatoms selected from N, O and/or S, which may be attached via a    heteroatom if feasible, or a carbon atom; preferred heteroatoms are    N or O; also preferred are piperidine, morpholine, pyrrolidine and    piperazine; with the most preferred (C₂₋₆)heterocycloalkyl being    pyrrolidine; the heterocycloalkyl group may be attached via a    heteroatom if feasible;-   (C₃₋₇)heterocycloalkyl means a heterocycloalkyl group having 3-7    carbon atoms, preferably 3-5 carbon atoms, and one or two    heteroatoms selected from N, O and/or S. Preferred heteroatoms are N    or O; preferred (C₃₋₇) heterocycloalkyl groups are azetidinyl,    pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl; more    preferred (C₃₋₇)heterocycloalkyl groups are piperidine, morpholine    and pyrrolidine; and the heterocycloalkyl group may be attached via    a heteroatom if feasible;-   (C₃₋₇)cycloalkoxy means a cycloalkyl group having 3-7 carbon atoms,    with the same meaning as previously defined, attached via a ring    carbon atom to an exocyclic oxygen atom;-   (C₆₋₁₀)aryl means an aromatic hydrocarbon group having 6-10 carbon    atoms, such as phenyl, naphthyl, tetrahydronaphthyl or indenyl; the    preferred (C₆₋₁₀)aryl group is phenyl;-   (C₁₋₅)heteroaryl means a substituted or unsubstituted aromatic group    having 1-5 carbon atoms and 1-4 heteroatoms selected from N, O    and/or S; the (C₁₋₅)heteroaryl may optionally be substituted;    preferred (C₁₋₅)heteroaryl groups are tetrazolyl, imidazolyl,    thiadiazolyl, pyridyl, pyrimidyl, triazinyl, thienyl or furyl, a    more preferred (C₁₋₅)heteroaryl is pyrimidyl;-   (C₁₋₉)heteroaryl means a substituted or unsubstituted aromatic group    having 1-9 carbon atoms and 1-4 heteroatoms selected from N, O    and/or S; the (C₁₋₉)heteroaryl may optionally be substituted;    preferred (C₁₋₉)heteroaryl groups are quinoline, isoquinoline and    indole;-   [(C₁₋₄)alkyl]amino means an amino group, monosubstituted with an    alkyl group containing 1-4 carbon atoms having the same meaning as    previously defined; preferred [(C₁₋₄)alkyl]amino group is    methylamino;-   di[(C₁₋₄)alkyl]amino means an amino group, disubstituted with alkyl    group(s), each containing 1-4 carbon atoms and having the same    meaning as previously defined; preferred di[(C₁₋₄)alkyl]amino group    is dimethylamino;-   halogen means fluorine, chlorine, bromine or iodine;-   (C₁₋₃)alkyl-C(O)—S—(C₁₋₃)alkyl means an alkyl-carbonyl-thio-alkyl    group, each of the alkyl groups having 1 to 3 carbon atoms with the    same meaning as previously defined;-   (C₃₋₇)cycloalkenyl means a cycloalkenyl group having 3-7 carbon    atoms, preferably 5-7 carbon atoms; preferred (C₃₋₇)cycloalkenyl    groups are cyclopentenyl or cyclohexenyl; cyclohexenyl groups are    most preferred;-   (C₂₋₆)heterocycloalkenyl means a heterocycloalkenyl group having 2-6    carbon atoms, preferably 3-5 carbon atoms; and 1 heteroatom selected    from N, O and/or S; preferred (C₂₋₆)heterocycloalkenyl groups are    oxycyclohexenyl and azacyclohexenyl group.-   In the above definitions with multifunctional groups, the attachment    point is at the last group.-   When, in the definition of a substituent, is indicated that “all of    the alkyl groups” of said substituent are optionally substituted,    this also includes the alkyl moiety of an alkoxy group.-   A circle in a ring of Formula (XVII) indicates that the ring is    aromatic.-   Depending on the ring formed, the nitrogen, if present in X or Y,    may carry a hydrogen.

In an exemplary embodiment of Formula (XVII), B₁ is C(R₇); B₂ is C(R₈);B₃ is C(R₉); B₄ is C(R₁₀); R₇, R₉, and R₁₀ are each H; and R₈ ishydrogen or methyl.

In an exemplary embodiment of Formula (XVII), the ring containing X, Yand Z is selected from the group consisting of pyridyl, pyrimidyl,pyridazyl, triazinyl, thiazolyl, oxazolyl and isoxazolyl.

In an exemplary embodiment of Formula (XVII), the ring containing X, Yand Z is selected from the group consisting of pyridyl, pyrimidyl andpyridazyl.

In an exemplary embodiment of Formula (XVII), the ring containing X, Yand Z is selected from the group consisting of pyridyl and pyrimidyl.

In an exemplary embodiment of Formula (XVII), the ring containing X, Yand Z is pyridyl.

In an exemplary embodiment of Formula (XVII), R₅ is selected from thegroup consisting of hydrogen, fluorine, methyl, methoxy andtrifluoromethyl.

In an exemplary embodiment of Formula (XVII), R₅ is hydrogen.

In an exemplary embodiment of Formula (XVII), R₂ and R₃ together form aheterocycloalkyl ring selected from the group consisting of azetidinyl,pyrrolidinyl, piperidinyl, homopiperidinyl and morpholinyl, optionallysubstituted with one or more of fluoro, hydroxyl, (C₁₋₃)alkyl and(C₁₋₃)alkoxy.

In an exemplary embodiment of Formula (XVII), R₂ and R₃ together form aheterocycloalkyl ring selected from the group consisting of azetidinyl,pyrrolidinyl and piperidinyl.

In an exemplary embodiment of Formula (XVII), R₂ and R₃ together form apyrrolidinyl ring.

In an exemplary embodiment of Formula (XVII), R₁ is independentlyselected from the group consisting of (C₁₋₆)alkyl, (C₂₋₆)alkenyl or(C₂₋₆)alkynyl, each optionally substituted with one or more substituentsselected from the group consisting of hydroxyl, (C₁₋₄)alkyl,(C₃₋₇)cycloalkyl, [(C₁₋₄)alkyl]amino, di[(C₁₋₄)alkyl] amino,(C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl and (C₃₋₇)heterocycloalkyl.

In an exemplary embodiment of Formula (XVII), B₁, B₂, B₃ and B₄ are CH;X is N; Y and Z are CH; R₅ is CH₃; A is N; R₂, R₃ and R₄ are H; and R₁is CO—CH₃.

In an exemplary embodiment of Formula (XVII), B₁, B₂, B₃ and B₄ are CH;X and Y are N; Z is CH; R₅ is CH₃; A is N; R₂, R₃ and R₄ are H; and R₁is CO—CH₃.

In an exemplary embodiment of Formula (XVII), B₁, B₂, B₃ and B₄ are CH;X and Y are N; Z is CH; R₅ is CH₃; A is CH; R₂ and R₃ together form apiperidinyl ring; R₄ is H; and R₁ is CO-ethenyl.

In an exemplary embodiment of Formula (XVII), B₁, B₂, B₃ and B₄ are CH;X, Y and Z are CH; R₅ is H; A is CH; R₂ and R₃ together form apyrrolidinyl ring; R₄ is H; and R₁ is CO-propynyl.

In an exemplary embodiment of Formula (XVII), B₁, B₂, B₃ and B₄ are CH;X, Y and Z are CH; R₅ is CH₃; A is CH; R₂ and R₃ together form apiperidinyl ring; R₄ is H; and R₁ is CO-propynyl.

In an exemplary embodiment of Formula (XVII), B₁, B₂, B₃ and B₄ are CH;X and Y are N; Z is CH; R₅ is H; A is CH; R₂ and R₃ together form amorpholinyl ring; R₄ is H; and R₁ is CO-ethenyl.

In an exemplary embodiment of Formula (XVII), B₁, B₂, B₃ and B₄ are CH;X and Y are N; Z is CH; R₅ is CH₃; A is CH; R₂ and R₃ together form amorpholinyl ring; R₄ is H; and R₁ is CO-propynyl.

In an exemplary preferred embodiment, the BTK inhibitor is a compound ofFormula (XVIII):

which is(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide,or a pharmaceutically-acceptable salt thereof. The preparation of thiscompound is described at Example 6 of International Patent ApplicationPublication No. WO 2013/010868. The preparation of this compound andrelated structures are described in the Examples of International PatentApplication Publication No. WO 2013/010868.

In an exemplary embodiment, the BTK inhibitor is(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamideor pharmaceutically-acceptable salt thereof.

In an exemplary embodiment, the BTK inhibitor is a compound of Formula(XIX) or a pharmaceutically-acceptable salt of a compound of Formula(XIX):

-   In Formula (XIX) the substituents are defined as:-   X is CH, N, O or S;-   Y is C(R₆), N, O or S;-   Z is CH, N or bond;-   A is CH or N;-   B₁ is N or C(R₇);-   B₂ is N or C(R₈);-   B₃ is N or C(R₉);-   B₄ is N or C(R₁₀);-   R₁ is R₁₁C(O), R₁₂S(O), R₁₃SO₂ or (C₁₋₆)alkyl optionally substituted    with R₁₄;-   R₂ is H, (C₁₋₃)alkyl or (C₃₋₇)cycloalkyl;-   R₃ is H, (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl); or-   R₂ and R₃ form, together with the N and C atom they are attached to,    a (C₃₋₇)heterocycloalkyl optionally substituted with one or more    fluorine, hydroxyl, (C₁₋₃)alkyl, (C₁₋₃)alkoxy or oxo;-   R₄ is H or (C₁₋₃)alkyl;-   R₅ is H, halogen, cyano, (C₁₋₄)alkyl, (C₁₋₃)alkoxy,    (C₃₋₆)cycloalkyl; all alkyl groups of R₅ are optionally substituted    with one or more halogen; or R₅ is (C₆₋₁₀)aryl or    (C₂₋₆)heterocycloalkyl;-   R₆ is H or (C₁₋₃)alkyl; or R₅ and R₆ together may form a    (C₃₋₇)cycloalkenyl, or (C₂₋₆)heterocycloalkenyl; each optionally    substituted with (C₁₋₃)alkyl, or one or more halogen;-   R₇ is H, halogen, CF₃, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;-   R₈ is H, halogen, CF₃, (C₁₋₃)alkyl or (C₁₋₃)alkoxy; or-   R₇ and R₈ together with the carbon atoms they are attached to, form    (6-10C.)aryl or (1-5C)heteroaryl;-   R₉ is H, halogen, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;-   R₁₀ is H, halogen, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;-   R₁₁ is independently selected from a group consisting of    (C₁₋₆)alkyl, (C₂₋₆)alkenyl and (C₂₋₆) alkynyl each alkyl, alkenyl or    alkynyl optionally substituted with one or more groups selected from    hydroxyl, (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl, [(C₁₋₄)alkyl]amino,    di[(C₁₋₄) alkyl]amino, (C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl    or (C₃₋₇)heterocycloalkyl, or-   R₁₁ is (C₁₋₃)alkyl-C(O)—S—(C₁₋₃)alkyl; or-   R₁₁ is (C₁₋₅)heteroaryl optionally substituted with one or more    groups selected from halogen or cyano.-   R₁₂ and R₁₃ are independently selected from a group consisting of    (C₂₋₆)alkenyl or (C₂₋₆)alkynyl both optionally substituted with one    or more groups selected from hydroxyl, (C₁₋₄)alkyl,    (C₃₋₇)cycloalkyl, [(C₁₋₄)alkyl]amino, di[(C₁₋₄)alkyl]amino,    (C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀) aryl, or    (C₃₋₇)heterocycloalkyl; or-   (C₁₋₅)heteroaryl optionally substituted with one or more groups    selected from halogen or cyano;-   R₁₄ is independently selected from a group consisting of halogen,    cyano or (C₂₋₆)alkenyl or (C₂₋₆) alkynyl both optionally substituted    with one or more groups selected from hydroxyl, (C₁₋₄) alkyl,    (C₃₋₇)cycloalkyl, [(C₁₋₄)alkyl]amino, di[(C₁₋₄)alkyl]amino,    (C₁₋₃)alkoxy, (C₃₋₇) cycloalkoxy, (C₆₋₁₀)aryl, (C₁₋₅)heteroaryl or    (C₃₋₇)heterocycloalkyl;-   with the proviso that    -   0 to 2 atoms of X, Y, Z can simultaneously be a heteroatom;    -   when one atom selected from X, Y is O or S, then Z is a bond and        the other atom selected from X, Y can not be O or S;    -   when Z is C or N then Y is C(R₆) or N and X is C or N;    -   0 to 2 atoms of B₁, B₂, B₃ and B₄ are N;-   with the terms used having the following meanings:-   (C₁₋₃)alkyl means a branched or unbranched alkyl group having 1-3    carbon atoms, being methyl, ethyl, propyl or isopropyl;-   (C₁₋₄)alkyl means a branched or unbranched alkyl group having 1-4    carbon atoms, being methyl, ethyl, propyl, isopropyl, butyl,    isobutyl, sec-butyl and tert-butyl, (C₁₋₃)alkyl groups being    preferred;-   (C₁₋₆)alkyl means a branched or unbranched alkyl group having 1-6    carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl,    tert-butyl, n-pentyl and n-hexyl. (C₁₋₅)alkyl groups are preferred,    (C₁₋₄)alkyl being most preferred;-   (C₁₋₂)alkoxy means an alkoxy group having 1-2 carbon atoms, the    alkyl moiety having the same meaning as previously defined;-   (C₁₋₃)alkoxy means an alkoxy group having 1-3 carbon atoms, the    alkyl moiety having the same meaning as previously defined, with    (C₁₋₂)alkoxy groups preferred;-   (C₂₋₃)alkenyl means an alkenyl group having 2-3 carbon atoms, such    as ethenyl or 2-propenyl;-   (C₂₋₄)alkenyl means a branched or unbranched alkenyl group having    2-4 carbon atoms, such as ethenyl, 2-propenyl, isobutenyl or    2-butenyl;-   (C₂₋₆)alkenyl means a branched or unbranched alkenyl group having    2-6 carbon atoms, such as ethenyl, 2-butenyl, and n-pentenyl, with    (C₂₋₄)alkenyl groups preferred, and (C₂₋₃)alkenyl groups even more    preferred;-   (C₂₋₄)alkynyl means a branched or unbranched alkynyl group having    2-4 carbon atoms, such as ethynyl, 2-propynyl or 2-butynyl;-   (C₂₋₃)alkynyl means an alkynyl group having 2-3 carbon atoms, such    as ethynyl or 2-propynyl;-   (C₂₋₆)alkynyl means a branched or unbranched alkynyl group having    2-6 carbon atoms, such as ethynyl, propynyl, n-butynyl, n-pentynyl,    isopentynyl, isohexynyl or n-hexynyl, with (C₂₋₄) alkynyl groups    preferred, and (2-3C)alkynyl groups more preferred;-   (C₃₋₆)cycloalkyl means a cycloalkyl group having 3-6 carbon atoms,    being cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;-   (C₃₋₇)cycloalkyl means a cycloalkyl group having 3-7 carbon atoms,    being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or    cycloheptyl;-   (C₂₋₆)heterocycloalkyl means a heterocycloalkyl group having 2-6    carbon atoms, preferably 3-5 carbon atoms, and one or two    heteroatoms selected from N, O and/or S, which may be attached via a    heteroatom if feasible, or a carbon atom; preferred heteroatoms are    N or O; preferred groups are piperidine, morpholine, pyrrolidine and    piperazine; a most preferred (C₂₋₆)heterocycloalkyl is pyrrolidine;    and the heterocycloalkyl group may be attached via a heteroatom if    feasible;-   (C₃₋₇)heterocycloalkyl means a heterocycloalkyl group having 3-7    carbon atoms, preferably 3-5 carbon atoms, and one or two    heteroatoms selected from N, O and/or S; preferred heteroatoms are N    or O; preferred (C₃₋₇) heterocycloalkyl groups are azetidinyl,    pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl; more    preferred (C₃₋₇)heterocycloalkyl groups are piperidine, morpholine    and pyrrolidine; even more preferred are piperidine and pyrrolidine;    and the heterocycloalkyl group may be attached via a heteroatom if    feasible;-   (C₃₋₇)cycloalkoxy means a cycloalkyl group having 3-7 carbon atoms,    with the same meaning as previously defined, attached via a ring    carbon atom to an exocyclic oxygen atom;-   (C₆₋₁₀)aryl means an aromatic hydrocarbon group having 6-10 carbon    atoms, such as phenyl, naphthyl, tetrahydronaphthyl or indenyl; the    preferred (C₆₋₁₀)aryl group is phenyl;-   (C₁₋₅)heteroaryl means a substituted or unsubstituted aromatic group    having 1-5 carbon atoms and 1-4 heteroatoms selected from N, O    and/or S, wherein the (C₁₋₅)heteroaryl may optionally be    substituted; preferred (C₁₋₅)heteroaryl groups are tetrazolyl,    imidazolyl, thiadiazolyl, pyridyl, pyrimidyl, triazinyl, thienyl or    furyl, and the more preferred (C₁₋₅) heteroaryl is pyrimidyl;-   [(C₁₋₄)alkyl]amino means an amino group, monosubstituted with an    alkyl group containing 1-4 carbon atoms having the same meaning as    previously defined; the preferred [(C₁₋₄) alkyl]amino group is    methylamino;-   di[(C₁₋₄)alkyl]amino means an amino group, disubstituted with alkyl    group(s), each containing 1-4 carbon atoms and having the same    meaning as previously defined; the preferred di[(C₁₋₄) alkyl]amino    group is dimethylamino;-   halogen means fluorine, chlorine, bromine or iodine;-   (C₁₋₃)alkyl-C(O)—S—(C₁₋₃)alkyl means an alkyl-carbonyl-thio-alkyl    group, each of the alkyl groups having 1 to 3 carbon atoms with the    same meaning as previously defined;-   (C₃₋₇)cycloalkenyl means a cycloalkenyl group having 3-7 carbon    atoms, preferably 5-7 carbon atoms; preferred (C₃₋₇)cycloalkenyl    groups are cyclopentenyl or cyclohexenyl; and cyclohexenyl groups    are most preferred;-   (C₂₋₆)heterocycloalkenyl means a heterocycloalkenyl group having 2-6    carbon atoms, preferably 3-5 carbon atoms; and 1 heteroatom selected    from N, O and/or S; the preferred (C₂₋₆) heterocycloalkenyl groups    are oxycyclohexenyl and azacyclohexenyl groups.-   In the above definitions with multifunctional groups, the attachment    point is at the last group.-   When, in the definition of a substituent, is indicated that “all of    the alkyl groups” of said substituent are optionally substituted,    this also includes the alkyl moiety of an alkoxy group.-   A circle in a ring of Formula (XIX) indicates that the ring is    aromatic.-   Depending on the ring formed, the nitrogen, if present in X or Y,    may carry a hydrogen.

In one embodiment the invention provides a compound according to FormulaXIX, wherein B₁ is C(R₇); B₂ is C(R₈); B₃ is C(R₉) and B₄ is C(R₁₀).

In an exemplary embodiment, the BTK inhibitor is a compound of Formula(XX):

-   or a pharmaceutically acceptable salt thereof,-   wherein:-   L_(a) is CH₂, O, NH or S;-   Ar is a substituted or unsubstituted aryl, or a substituted or    unsubstituted heteroaryl;-   Y is an optionally substituted group selected from the group    consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl    and heteroaryl;-   Z is C(═O), OC(═O), NRC(═O), C(═S), S(═O)_(x), OS(═O)_(x) or    NRS(═O)_(x), where x is 1 or 2;-   R⁷ and R⁸ are each independently H; or R⁷ and R⁸ taken together form    a bond;-   R⁶ is H; and-   R is H or C₁-C₆alkyl.

In an exemplary embodiment, the BTK inhibitor is ibrutinib or apharmaceutically-acceptable salt thereof. In an exemplary embodiment,the BTK inhibitor is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.In an exemplary embodiment, the BTK inhibitor is1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one.In an exemplary embodiment, the BTK inhibitor is(S)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.In an exemplary embodiment, the BTK inhibitor has the structure ofFormula (XX-A), or an enantiomer thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

In an exemplary embodiment, the BTK inhibitor is a compound of Formula(XXI):

-   or a pharmaceutically acceptable salt thereof,-   wherein:-   L_(a) is CH₂, O, NH or S;-   Ar is a substituted or unsubstituted aryl, or a substituted or    unsubstituted heteroaryl;-   Y is an optionally substituted group selected from the group    consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl    and heteroaryl;-   Z is C(═O), OC(═O), NRC(═O), C(═S), S(═O)_(x), OS(═O)_(x) or    NRS(═O)_(x), where x is 1 or 2;-   R⁷ and R⁸ are each H; or R⁷ and R⁸ taken together form a bond;-   R⁶ is H; and-   R is H or C₁-C₆alkyl.

In an exemplary embodiment, the BTK inhibitor is a compound of Formula(XXII):

-   or a pharmaceutically acceptable salt thereof,-   wherein:-   L_(a) is CH₂, O, NH or S;-   Ar is a substituted or unsubstituted aryl, or a substituted or    unsubstituted heteroaryl;-   Y is an optionally substituted group selected from the group    consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl    and heteroaryl;-   Z is C(═O), OC(═O), NRC(═O), C(═S), S(═O)_(x), OS(═O)_(x) or    NRS(═O)_(x), where x is 1 or 2;-   R⁷ and R⁸ are each H; or R⁷ and R⁸ taken together form a bond;-   R⁶ is H; and-   R is H or C₁-C₆alkyl.

In an exemplary embodiment, the BTK inhibitor is a compound of Formula(XXIII):

-   or a pharmaceutically acceptable salt thereof,-   wherein:-   L_(a) is CH₂, O, NH or S;-   Ar is a substituted or unsubstituted aryl, or a substituted or    unsubstituted heteroaryl;-   Y is an optionally substituted group selected from the group    consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl    and heteroaryl;-   Z is C(═O), OC(═O), NRC(═O), C(═S), S(═O)_(x), OS(═O)_(x) or    NRS(═O)_(x), where x is 1 or 2;-   R⁷ and R⁸ are each H; or R⁷ and R⁸ taken together form a bond;-   R⁶ is H; and-   R is H or C₁-C₆alkyl.

In an exemplary embodiment, the BTK inhibitor is a compound of Formula(XXIV):

-   or a pharmaceutically acceptable salt thereof,-   wherein:-   Q¹ is aryl¹, heteroaryl¹, cycloalkyl, heterocyclyl, cycloalkenyl, or    heterocycloalkenyl, any of which is optionally substituted by one to    five independent G¹ substituents;-   R¹ is alkyl, cycloalkyl, bicycloalkyl, aryl, heteroaryl, aralkyl,    heteroaralkyl, heterocyclyl, or heterobicycloalkyl, any of which is    optionally substituted by one or more independent G¹¹ substituents;-   G¹ and G⁴¹ are each independently halo, oxo, —CF₃, —OCF₃, —OR²,    —NR²R³(R^(3a))_(j1), —C(O)R², —CO₂R², —CONR²R³, —NO₂, —CN,    —S(O)_(j1)R², —SO₂NR²R³, NR²(C═O)R³, NR²(C═O)OR³, NR²(C═O)NR²R³,    NR²S(O)_(j1)R³, —(C═S)OR², —(C═O)SR², —NR²(C═NR³)NR^(2a)R^(3a),    —NR²(C═NR³)OR^(2a), —NR²(C═NR³)SR^(3a), —O(C═O)OR², —O(C═O)NR²R³,    —O(C═O)SR², —S(C═O)OR², —S(C═O)NR²R³, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,    C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,    C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,    C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,    cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,    cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,    cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,    cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,    heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of    which is optionally substituted with one or more independent halo,    oxo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³(R^(333a))_(j1a), —C(O)R²²²,    —CO₂R²²², —CONR²²²R³³³, —NO₂, —CN, —S(O)_(j1a)R²²², —SO₂NR²²²R³³³,    NR²²²(C═O)R³³³, NR²²²(C═O)OR³³³, NR²²²(C═O)NR²²²R³³³,    NR²²²S(O)_(j1a)R³³³, —(C═S)OR²²², —(C═O)SR²²²,    —NR²²²(C═NR³³³)NR^(222a)R^(333a), NR²²²(C═NR³³³)OR^(222a),    —NR²²²(C═NR³³³)SR^(333a), —O(C═O)OR²²², —O(C═O)NR²²²R³³³,    —O(C═O)SR²²², —S(C═O)OR²²², or —S(C═O)NR²²²R³³³ substituents; or    —(X¹)_(n)—(Y¹)_(m)—R⁴; Or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or    aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with one    or more independent halo, —CF₃, —OCF₃, —OR²²²,    —NR²²²R³³³(R^(333a))_(j2a), —C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —NO₂,    —CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, NR²²²(C═O)R³³³,    NR²²²(C═O)OR³³³, NR²²²(C═O)NR²²²R³³³, NR²²²S(O)_(j2a)R³³³,    —(C═S)OR²²², —(C═O)SR²²², —NR²²²(C═NR³³³)NR^(222a)R^(333a),    —NR²²²(C═NR³³³)OR^(222a), —NR²²²(C═NR³³³)SR^(333a), O(C═O)OR²²²,    —O(C═O)NR²²²R³³³, —O(C═O)SR²²², —S(C═O)OR²²², or —S(C═O)NR²²²R³³³    substituents; or hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or    hetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted with    one or more independent halo, —CF₃, —OCF₃, —OR²²², —NR²²²,    R³³³(R^(333a))_(j3a), —C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —NO₂, —CN,    —S(O)_(j3a)R²²², —SO₂NR²²²R³³³, NR²²²(C═O)R³³³, NR²²²(C═O)OR³³³,    NR²²²(C═O)NR²²²R³³³, NR²²²S(O)_(j3a)R³³³, —(C═S)OR²²², —(C═O)SR²²²,    —NR²²²(C═NR³³³)NR²²²aR³³³a, —NR²²²(C═NR³³³)OR^(222a)    NR²²²(C═NR³³³)SR³³³a, —O(C═O)OR²²², O(C═O)NR²²²R³³³, —O(C═O)SR²²²,    —S(C═O)OR²²², or —S(C═O)NR²²²R³³³ substituents;-   G¹¹ is halo, oxo, —CF₃, —OCF₃, —OR²¹, —NR²¹R³¹(R^(3a1))_(j4),    —C(O)R²¹, —CO₂R²¹, —CONR²¹R³¹, —NO₂, —CN, —S(O)_(j4)R²¹,    —SO₂NR²¹R³¹, NR²¹(C═O)R³¹, NR²¹(C═O)OR³¹, NR²¹(C═O)NR²¹R³¹,    NR²¹S(O)_(j4)R³¹, —(C═S)OR²¹, —(C═O)SR²¹, —NR²¹    (C═NR³¹)NR^(2a1)R^(3a1), —NR²¹(C═NR³¹)OR^(2a1),    —NR²¹(C═NR³¹)SR^(3a1), —O(C═O)OR²¹, —O(C═O)NR²¹R³¹, —O(C═O)SR²¹,    —S(C═O)OR²¹, —S(C═O)NR²¹R³¹, —P(O)OR²¹OR³¹, C₀₋₁₀alkyl,    C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,    C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,    C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,    C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,    cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,    cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,    cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,    heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, or    heterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted    with one or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,    —NR²²²¹R³³³¹(R^(333a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹,    —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹,    NR²²²¹(C═O)R³³³¹, NR²²²¹(C═O)OR³³³¹, NR²²²¹(C═O)NR²²²¹R³³³¹,    NR²²²¹S(O)_(j4a)R³³³¹, —(C═S)OR²²²¹, —(C═O)SR²²²¹,    —NR²²²¹(C═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹(C═N³³³¹)OR^(222a1),    —NR²²²¹(C═NR³³³¹)SR^(333a1), —O(C═O)OR²²²¹, —O(C═O)NR²²²¹R³³³¹,    —O(C═O)SR²²²¹, —S(C═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or    —S(C═O)NR²²²¹R³³³¹ substituents; or aryl-C₀₋₁₀alkyl,    aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is optionally    substituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²¹,    —NR²²²¹R³³³¹(R^(333a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹,    —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹, SO₂NR²²²¹R³³³¹,    NR²²²¹(C═O)R³³³¹, NR²²²¹(C═O)OR³³³¹, NR²²²¹(C═O)NR²²²¹R³³¹,    NR²²²¹S(O)_(j5a)R³³³¹, —(C═S)OR²²²¹, —(C═O)SR²²²¹,    —NR²²²¹(C═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹(C═NR³³³¹)OR^(222a1),    —NR²²²¹(C═NR³³³¹)SR^(333a1), —O(C═O)OR²²²¹, —O(C═O)NR²²²¹R³³³¹,    —O(C═O)SR²²²¹, —S(C═O)OR²²²¹, —P(O)OR²²²¹R³³³¹, or    —S(C═O)NR²²²¹R³³³¹ substituents; or hetaryl-C₀₋₁₀alkyl,    hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which is    optionally substituted with one or more independent halo, —CF₃,    —OCF₃, —OR²²²¹, NR²²²¹R³³³¹(R^(333a1))_(j6a), —C(O)R²²²¹, —CO₂R²²²¹,    —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j6a)R²²²¹, SO₂NR²²²¹R³³³¹,    NR²²²¹(C═O)R³³³¹, NR²²²¹(C═O)OR³³³¹, NR²²²¹(C═O)NR²²²¹R³³³¹,    NR²²²¹S(O)_(j6a)R³³³¹, —(C═S)OR²²²¹, —(C═O)SR²²²¹,    NR²²²¹(C═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹(C═NR³³³¹)OR^(222a1),    —NR²²²¹(C═NR³³³¹)SR^(333a1), —O(C═O)OR²²²¹, —O(C═O)NR²²²¹R³³³¹,    —O(C═O)SR²²²¹, —S(C═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or    —S(C═O)NR²²²¹R³³³¹ substituents; or G¹¹ is taken together with the    carbon to which it is attached to form a double bond which is    substituted with R⁵ and G¹¹¹;-   R², R^(2a), R³, R^(3a), R²²², R²²²a, R³³³, R^(333a), R²¹, R^(2a1),    R³¹, R^(3a1), R²²²¹, R^(222a1), R³³³¹, and R^(333a1) are each    independently equal to C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,    C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,    C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,    C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,    cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,    cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,    cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,    cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,    heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of    which is optionally substituted by one or more G¹¹¹ substituents; or    aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl,    hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl,    any of which is optionally substituted by one or more G¹¹¹    substituents; or in the case of —NR²R³(R^(3a))_(j1) or    —NR²²²R³³³(R³³³a)_(j1a) or —NR²²²R³³³(R^(333a))_(j2a) or    —NR²²²¹R³³³¹(R^(333a1))_(j3a) or —NR²²²¹R³³³¹(R^(333a1))_(j4a) or    —NR²²²¹R³³³¹(R^(333a1))_(j5a) or —NR²²²¹R³³³¹(R^(333a1))_(j6a), R²    and R³ or R²²² and R³³³3 or R²²²¹ and R³³³¹ taken together with the    nitrogen atom to which they are attached form a 3-10 membered    saturated ring, unsaturated ring, heterocyclic saturated ring, or    heterocyclic unsaturated ring, wherein said ring is optionally    substituted by one or more G¹¹¹ substituents;-   X¹ and Y¹ are each independently —O—, —NR⁷—, —S(O)_(j7)—, —CR⁵R⁶—,    —N(C(O)OR⁷)—, —N(C(O)R⁷)—, —N(SO₂R⁷)—, —CH₂O—, —CH₂S—, —CH₂N(R⁷)—,    —CH(NR⁷)—, —CH₂N(C(O)R⁷)—, —CH₂N(C(O)OR⁷)—, —CH₂N(SO₂R⁷)—,    —CH(NHR⁷)—, —CH(NHC(O)R⁷)—, —CH(NHSO₂R⁷)—, —CH(NHC(O)OR⁷)—,    —CH(OC(O)R⁷)—, —CH(OC(O)NHR⁷)—, —CH═CH—, —C.ident.C—, —C(═NOR⁷)—,    —C(O)—, —CH(OR⁷)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—, —N(R⁷)S(O)—,    —N(R⁷)S(O)₂— —OC(O)N(R⁷)—, —N(R⁷)C(O)N(R⁷)—, —NR⁷C(O)O—,    —S(O)N(R⁷)—, —S(O)₂N(R⁷)—, —N(C(O)R⁷)S(O)—, —N(C(O)R⁷)S(O)₂—,    —N(R⁷)S(O)N(R⁷)—, —N(R⁷)S(O)₂N(R⁷)—, —C(O)N(R⁷)C(O)—,    —S(O)N(R⁷)C(O)—, —S(O)₂N(R⁷)C(O)—, —OS(O)N(R⁷)—, —OS(O)₂N(R⁷)—,    —N(R⁷)S(O)O—, —N(R⁷)S(O)₂O—, —N(R⁷)S(O)C(O)—, —N(R⁷)S(O)₂C(O)—,    —SON(C(O)R⁷)—, —SO₂N(C(O)R⁷)—, —N(R⁷)SON(R⁷)—, —N(R⁷)SO₂N(R⁷)—,    —C(O)O—, —N(R⁷)P(OR⁸)O—, —N(R⁷)P(OR⁸)—, —N(R⁷)P(O)(OR⁸)O—,    —N(R⁷)P(O)(OR⁸)—, —N(C(O)R⁷)P(OR⁸)O—, —N(C(O)R⁷)P(OR⁸)—,    —N(C(O)R⁷)P(O)(OR⁸)O—, —N(C(O)R⁷)P(OR⁸)—, —CH(R⁷)S(O)—,    —CH(R⁷)S(O)₂—, —CH(R⁷)N(C(O)OR⁷)—, —CH(R⁷)N(C(O)R⁷)—,    —CH(R⁷)N(SO₂R⁷)—, —CH(R⁷)O—, —CH(R⁷)S—, —CH(R⁷)N(R⁷)—,    —CH(R⁷)N(C(O)R⁷)—, —CH(R⁷)N(C(O)OR⁷)—, —CH(R⁷)N(SO₂R⁷)—,    —CH(R⁷)C(═NOR⁷)—, —CH(R⁷)C(O)—, —CH(R⁷)CH(OR⁷)—, —CH(R⁷)C(O)N(R⁷)—,    —CH(R⁷)N(R⁷)C(O)—, —CH(R⁷)N(R⁷)S(O)—, —CH(R⁷)N(R⁷)S(O)₂—,    —CH(R⁷)OC(O)N(R⁷)—, —CH(R⁷)N(R⁷)C(O)N(R⁷)—, —CH(R⁷)NR⁷C(O)O—,    —CH(R⁷)S(O)N(R⁷)—, —CH(R⁷)S(O)₂N(R⁷)—, —CH(R⁷)N(C(O)R⁷)S(O)—,    —CH(R⁷)N(C(O)R⁷)S(O)—, —CH(R⁷)N(R⁷)S(O)N(R⁷)—,    —CH(R⁷)N(R⁷)S(O)₂N(R⁷)—, —CH(R⁷)C(O)N(R⁷)C(O)—,    —CH(R⁷)S(O)N(R⁷)C(O)—, —CH(R⁷)S(O)₂N(R⁷)C(O)—, —CH(R⁷)OS(O)N(R⁷)—,    —CH(R⁷)OS(O)₂N(R⁷)—, —CH(R⁷)N(R⁷)S(O)O—, —CH(R⁷)N(R⁷)S(O)₂O—,    —CH(R⁷)N(R⁷)S(O)C(O)—, —CH(R⁷)N(R⁷)S(O)₂C(O)—, —CH(R⁷)SON(C(O)R⁷)—,    —CH(R⁷)SO₂N(C(O)R⁷)—, —CH(R⁷)N(R⁷)SON(R⁷)—, —CH(R⁷)N(R⁷)SO₂N(R⁷)—,    —CH(R⁷)C(O)O—, —CH(R⁷)N(R⁷)P(OR⁸)O—, —CH(R⁷)N(R⁷)P(OR⁸)—,    —CH(R⁷)N(R⁷)P(O)(OR⁸)O—, —CH(R⁷)N(R⁷)P(O)(OR⁸)—,    —CH(R⁷)N(C(O)R⁷)P(OR⁸)O—, —CH(R⁷)N(C(O)R⁷)P(OR⁸)—,    —CH(R⁷)N(C(O)R⁷)P(O)(OR⁸)O—, or —CH(R⁷)N(C(O)R⁷)P(OR⁸)—;-   or X¹ and Y¹ are each independently represented by one of the    following structural formulas:

-   R¹⁰, taken together with the phosphinamide or phosphonamide, is a    5-, 6-, or 7-membered aryl, heteroaryl or heterocyclyl ring system;-   R⁵, R⁶, and G¹¹¹ are each independently a C₀₋₁₀alkyl, C₂₋₁₀alkenyl,    C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,    C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,    C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,    cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,    cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,    cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,    cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,    heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of    which is optionally substituted with one or more independent halo,    —CF₃, —OCF₃, —OR⁷⁷, —NR⁷⁷R⁸⁷, —C(O)R⁷⁷, —CO₂R⁷⁷, —CONR⁷⁷R⁸⁷, —NO₂,    —CN, —S(O)_(j5a)R⁷⁷, —SO₂NR⁷⁷R⁸⁷, NR⁷⁷(C═O)R⁸⁷, NR⁷⁷(C═O)OR⁸⁷,    NR⁷⁷(C═O)NR⁷⁸R⁸⁷, NR⁷⁷S(O)_(j5a)R⁸⁷, —(C═S)OR⁷⁷, —(C═O)SR⁷⁷,    —NR⁷⁷(C═NR⁷)NR⁷⁸R⁸⁸, —NR⁷⁷(C═NR⁸⁷)OR⁷⁸, —NR⁷⁷(C═NR⁸⁷)SR⁷⁸,    —O(C═O)OR⁷⁷, —O(C═O)NR⁷⁷R⁸⁷, —O(C═O)SR⁷⁷, —S(C═O)OR⁷⁷,    —P(O)OR⁷⁷OR⁸⁷, or —S(C═O)NR⁷⁷R⁸⁷ substituents; or aryl-C₀₋₁₀alkyl,    aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is optionally    substituted with one or more independent halo, —CF₃, —OCF₃, —OR⁷⁷,    —NR⁷⁷R⁸⁷, —C(O)R⁷⁷, —CO₂R⁷⁷, —CONR⁷⁷R⁸⁷, —NO₂, —CN, —S(O)_(j1a)R⁷⁷,    —SO₂NR⁷⁷R⁸⁷, NR⁷⁷(C═O)R⁸⁷, NR⁷⁷(C═O)OR⁸⁷, NR⁷⁷(C═O)NR⁷⁸R⁸⁷,    NR⁷⁷S(O)_(j5a)R⁸⁷, —(C═S)OR⁷⁷, —(C═O)SR⁷⁷, —NR⁷⁷(C═NR⁷)NR⁷⁸R⁸⁸,    —NR⁷⁷(C═NR⁸⁷)OR⁷⁸, —NR⁷⁷(C═NR⁸⁷)SR⁷⁸, —O(C═O)OR⁷⁷, —O(C═O)NR⁷⁷R⁸⁷,    —O(C═O)SR⁷⁷, —S(C═O)OR⁷⁷, —P(O)OR⁷⁷R⁸⁷, or —S(C═O)NR⁷⁷R⁸⁷    substituents; or hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or    hetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted with    one or more independent halo, —CF₃, —OCF₃, —OR, —NR⁷⁷R⁸⁷, C(O)R⁷⁷,    —CO₂R⁷⁷, —CONR⁷⁸R⁸⁷, —NO₂, —CN, —S(O)_(j5a)R⁷⁷, —SO₂NR⁷⁷R⁸⁷,    NR⁷⁷(C═O)R⁸⁷, NR⁷⁷(C═O)OR⁸⁷, NR⁷⁷(C═O)NR⁷⁸R⁸⁷, NR⁷⁷S(O)_(j5a)R⁸⁷,    —(C═S)OR⁷⁷, —(C═O)SR⁷⁷, —NR⁷⁷(C═NR⁸⁷)NR⁷⁸R⁸⁷, —NR⁷⁷(C═NR⁸⁷)OR⁷⁸,    —NR⁷⁷(C═NR⁸⁷)SR⁷⁸, —O(C═O)OR⁷⁷, —O(C═O)NR⁷⁷R⁸⁷, —O(C═O)SR⁷⁷,    —S(C═O)OR⁷⁷, —P(O)OR⁷⁷OR⁸⁷, or —S(C═O)NR⁷⁷R⁸⁷ substituents; or R⁵    with R⁶ taken together with the respective carbon atom to which they    are attached, form a 3-10 membered saturated or unsaturated ring,    wherein said ring is optionally substituted with R⁶⁹; or R⁵ with R⁶    taken together with the respective carbon atom to which they are    attached, form a 3-10 membered saturated or unsaturated heterocyclic    ring, wherein said ring is optionally substituted with R⁶⁹-   R⁷ and R⁸ are each independently H, acyl, alkyl, alkenyl, aryl,    heteroaryl, heterocyclyl or cycloalkyl, any of which is optionally    substituted by one or more G¹¹¹ substituents;-   R⁴ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,    heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is    optionally substituted by one or more G⁴¹ substituents;-   R⁶⁹ is equal to halo, —OR⁷⁸, —SH, —NR⁷⁸R⁸⁸, —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸,    —NO₂, —CN, —S(O)_(j8)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl, C₂₋₁₀alkenyl,    C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,    C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,    C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl,    cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl,    cycloC₃₋₈alkenylC₁₋₁₀alkyl, cycloC₃₋₈alkylC₂₋₁₀alkenyl,    cycloC₃₋₈alkenylC₂₋₁₀alkenyl, cycloC₃₋₈alkylC₂₋₁₀alkynyl,    cycloC₃₋₈alkenylC₂₋₁₀alkynyl, heterocyclyl-C₀₋₁₀alkyl,    heterocyclyl-C₂₋₁₀alkenyl, or heterocyclyl-C₂₋₁₀alkynyl, any of    which is optionally substituted with one or more independent halo,    cyano, nitro, —OR⁷⁷, —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents; or    aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of    which is optionally substituted with one or more independent halo,    cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,    haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,    C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸    substituents; or hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or    hetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted with    one or more independent halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl,    C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,    haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,    —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents; or    mono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,    mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl, or    —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally substituted    with one or more independent halo, cyano, nitro, —OR⁷⁷, C₁₋₁₀alkyl,    C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl,    haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸    SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the case of    —NR⁷⁸R⁸⁸, R⁷⁸ and R⁸⁸ taken together with the nitrogen atom to which    they are attached form a 3-10 membered saturated ring, unsaturated    ring, heterocyclic saturated ring, or heterocyclic unsaturated ring,    wherein said ring is optionally substituted with one or more    independent halo, cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷⁷⁸R⁸⁸⁸,    or —NR⁷⁷⁸R⁸⁸⁸ substituents;-   R⁷⁷, R⁷⁸, R⁸⁷, R⁸⁸, R⁷⁷⁸, and R⁸⁸⁸ are each independently    C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,    C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,    C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,    C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,    cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,    cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,    cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,    heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,    heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl,    C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,    C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,    diC₁₋₆alkylaminocarbonyl, mono(aryl)aminocarbonyl,    di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of    which is optionally substituted with one or more independent halo,    cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), or    —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or aryl-C₀₋₁₀alkyl,    aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is optionally    substituted with one or more independent halo, cyano, nitro,    —O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,    haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,    C₁₋₄alkoxycarbonyl, —CON(C₀₋₄alkyl)(C₀₋₁₀alkyl),    —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), or —N(C₀₋₄alkyl)(C₀₋₄alkyl)    substituents; or hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or    hetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted with    one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),    C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,    haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,    —CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), or    —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or    mono(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,    mono(aryl)aminoC₁₋₆alkyl, di(aryl)aminoC₁₋₆alkyl, or    —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which is optionally substituted    with one or more independent halo, cyano, nitro, —O(C₀₋₄alkyl),    C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,    haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,    —CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), or    —N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; and-   n, m, j1, j1a, j2a, j3a, j4, j4a, j5a, j6a, j7, and j8 are each    independently equal to 0, 1, or 2.

In an exemplary embodiment, the BTK inhibitor is a compound selectedfrom the structures disclosed in U.S. Pat. Nos. 8,450,335 and 8,609,679,and U.S. Patent Application Publication Nos. 2010/0029610 A1,2012/0077832 A1, 2013/0065879 A1, 2013/0072469 A1, and 2013/0165462 A1.In an exemplary embodiment, the BTK inhibitor is a compound of Formula(XXV) or Formula (XXVI):

-   or a pharmaceutically acceptable salt thereof, wherein:-   Ring A is an optionally substituted group selected from phenyl, a    3-7 membered saturated or partially unsaturated carbocyclic ring, an    8-10 membered bicyclic saturated, partially unsaturated or aryl    ring, a 5-6 membered monocyclic heteroaryl ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    a 4-7 membered saturated or partially unsaturated heterocyclic ring    having 1-3 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, a 7-10 membered bicyclic saturated or partially    unsaturated heterocyclic ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or an 8-10 membered    bicyclic heteroaryl ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen, or sulfur;-   Ring B is an optionally substituted group selected from phenyl, a    3-7 membered saturated or partially unsaturated carbocyclic ring, an    8-10 membered bicyclic saturated, partially unsaturated or aryl    ring, a 5-6 membered monocyclic heteroaryl ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    a 4-7 membered saturated or partially unsaturated heterocyclic ring    having 1-3 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, a 7-10 membered bicyclic saturated or partially    unsaturated heterocyclic ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or an 8-10 membered    bicyclic heteroaryl ring having 1-5 heteroatoms independently    selected from nitrogen, oxygen, or sulfur;-   R¹ is a warhead group;-   R^(y) is hydrogen, halogen, —CN, —CF₃, C₁₋₄ aliphatic, C₁₋₄    haloaliphatic, —OR, —C(O)R, or —C(O)N(R)₂;-   each R group is independently hydrogen or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered    heterocyclic ring having 1-2 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur;-   W¹ and W² are each independently a covalent bond or a bivalent C₁₋₃    alkylene chain wherein one methylene unit of W¹ or W² is optionally    replaced by —NR²—, —N(R²)C(O)—, —C(O)N(R²)—, —N(R²)SO₂—, —SO₂N(R²)—,    —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO₂—;-   R² is hydrogen, optionally substituted C₁₋₆ aliphatic, or —C(O)R,    or:-   R² and a substituent on Ring A are taken together with their    intervening atoms to form a 4-6 membered saturated, partially    unsaturated, or aromatic fused ring, or:-   R² and R^(y) are taken together with their intervening atoms to form    a 4-7 membered partially unsaturated or aromatic fused ring;-   m and p are independently 0-4; and-   R^(x) and R^(v) are independently selected from —R, halogen, —OR,    —O(CH₂)_(q)OR, —CN, —NO₂, —SO₂R, —SO₂N(R)₂, —SOR, —C(O)R, —CO₂R,    —C(O)N(R)₂, —NRC(O)R, —NRC(O)NR₂, —NRSO₂R, or —N(R)₂, wherein q is    1-4; or:-   R^(x) and R¹ when concurrently present on Ring B are taken together    with their intervening atoms to form a 5-7 membered saturated,    partially unsaturated, or aryl ring having 0-3 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, wherein    said ring is substituted with a warhead group and 0-3 groups    independently selected from oxo, halogen, —CN, or C₁₋₆ aliphatic; or-   R^(v) and R¹ when concurrently present on Ring A are taken together    with their intervening atoms to form a 5-7 membered saturated,    partially unsaturated, or aryl ring having 0-3 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, wherein    said ring is substituted with a warhead group and 0-3 groups    independently selected from oxo, halogen, —CN, or C₁₋₆ aliphatic.

In an exemplary embodiment, the BTK inhibitor is a compound of Formula(XXV) or Formula (XXVI), wherein:

Ring A is an optionally substituted group selected from phenyl, a 3-7membered saturated or partially unsaturated carbocyclic ring, an 8-10membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, a 7-10 memberedbicyclic saturated or partially unsaturated heterocyclic ring having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;Ring B is an optionally substituted group selected from phenyl, a 3-7membered saturated or partially unsaturated carbocyclic ring, an 8-10membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, a 7-10 memberedbicyclic saturated or partially unsaturated heterocyclic ring having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;R¹ is -L-Y, wherein:L is a covalent bond or a bivalent C₁₋₈ saturated or unsaturated,straight or branched, hydrocarbon chain, wherein one, two, or threemethylene units of L are optionally and independently replaced bycyclopropylene, —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO₂—, —SO₂N(R)—, —O—,—C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—, —C(═NR)—, —N═N—, or—C(═N₂)—;Y is hydrogen, C₁₋₆ aliphatic optionally substituted with oxo, halogen,or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partiallyunsaturated, or aryl ring having 0-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, and wherein said ring is substitutedwith at 1-4 groups independently selected from -Q-Z, oxo, NO₂, halogen,CN, or C₁₋₆ aliphatic, wherein:Q is a covalent bond or a bivalent C₁₋₆ saturated or unsaturated,straight or branched, hydrocarbon chain, wherein one or two methyleneunits of Q are optionally and independently replaced by —NR—, —S—, —O—,—C(O)—, —SO—, or —SO₂—; andZ is hydrogen or C₁₋₆ aliphatic optionally substituted with oxo,halogen, or CN;R^(y) is hydrogen, halogen, —CN, —CF₃, C₁₋₄ aliphatic, C₁₋₄haloaliphatic, —OR, —C(O)R, or —C(O)N(R)₂;each R group is independently hydrogen or an optionally substitutedgroup selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;W¹ and W² are each independently a covalent bond or a bivalent C₁₋₃alkylene chain wherein one methylene unit of W¹ or W² is optionallyreplaced by —NR²—, —N(R²)C(O)—, —C(O)N(R²)—, —N(R²)SO₂—, —SO₂N(R²), —O—,—C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO₂—;R² is hydrogen, optionally substituted C₁₋₆ aliphatic, or —C(O)R, or:R² and a substituent on Ring A are taken together with their interveningatoms to form a 4-6 membered partially unsaturated or aromatic fusedring; orR² and R^(y) are taken together with their intervening atoms to form a4-6 membered saturated, partially unsaturated, or aromatic fused ring;m and p are independently 0-4; andR^(x) and R^(v) are independently selected from —R, halogen, —OR,—O(CH₂)_(q)OR, —CN, —NO₂, —SO₂R, —SO₂N(R)₂, —SOR, —C(O)R, —CO₂R,—C(O)N(R)₂, —NRC(O)R, —NRC(O)NR₂, —NRSO₂R, or —N(R)₂, or:R^(x) and R¹ when concurrently present on Ring B are taken together withtheir intervening atoms to form a 5-7 membered saturated, partiallyunsaturated, or aryl ring having 0-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, wherein said ring is substituted witha warhead group and 0-3 groups independently selected from oxo, halogen,—CN, or C₁₋₆ aliphatic; orR^(v) and R¹ when concurrently present on Ring A are taken together withtheir intervening atoms to form a 5-7 membered saturated, partiallyunsaturated, or aryl ring having 0-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, wherein said ring is substituted witha warhead group and 0-3 groups independently selected from oxo, halogen,—CN, or C₁₋₆ aliphatic.As defined generally above, Ring A is an optionally substituted groupselected from phenyl, a 3-7 membered saturated or partially unsaturatedcarbocyclic ring, an 8-10 membered bicyclic saturated, partiallyunsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a 4-7 membered saturated or partially unsaturated heterocyclicring having 1-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, a 7-10 membered bicyclic saturated or partiallyunsaturated heterocyclic ring having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclicheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, Ring A is anoptionally substituted phenyl group. In some embodiments, Ring A is anoptionally substituted naphthyl ring or an optionally substitutedbicyclic 8-10 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In certainother embodiments, Ring A is an optionally substituted 3-7 memberedcarbocyclic ring. In yet other embodiments, Ring A is an optionallysubstituted 4-7 membered heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.In certain embodiments, Ring A is substituted as defined herein. In someembodiments, Ring A is substituted with one, two, or three groupsindependently selected from halogen, R^(o), or —(CH₂)₀₋₄OR^(o), or—O(CH₂)₀₋₄R^(o), wherein each R^(o) is an alkyl or aryl group. Exemplarysubstituents on Ring A include Br, I, Cl, methyl, —CF₃, —C≡CH,—OCH₂phenyl, OCH₂(fluorophenyl), or —OCH₂pyridyl.

In an exemplary embodiment, the BTK inhibitor is CC-292. In an exemplaryembodiment, the BTK inhibitor is a compound of Formula (XXVII):

which isN-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide,or a pharmaceutically acceptable salt thereof, in an exemplaryembodiment a hydrochloride salt or besylate salt thereof. Thepreparation of this compound is described in U.S. Patent ApplicationPublication No. 2010/0029610 A1 at Example 20. The preparation of thehydrochloride salt or besylate salt of this compound is described inU.S. Patent Application Publication No. 2012/0077832 A1.

In an exemplary embodiment, the BTK inhibitor isN-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamideor a pharmaceutically acceptable salt thereof, or a hydrochloride saltthereof. The preparation of this compound is described in U.S. PatentApplication Publication No. 2012/0077832 A1.

In an exemplary embodiment, the BTK inhibitor is(N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide),or a pharmaceutically acceptable salt thereof, or a besylate saltthereof. The preparation of this compound is described in U.S. PatentApplication Publication No. 2010/0029610 A1 at Example 20. Thepreparation of its besylate salt is described in U.S. Patent ApplicationPublication No. 2012/0077832 A1.

In an exemplary embodiment, the BTK inhibitor is a compound of Formula(XXVIII):

or a pharmaceutically acceptable salt thereof. In an exemplaryembodiment, the BTK inhibitor is the hydrochloride salt of a compound ofFormula (XXVIII). The preparation of this compound is described inInternational Patent Application Publication No. WO 2013/081016 A1. Inan exemplary embodiment, the BTK inhibitor is6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-oneor a pharmaceutically acceptable salt thereof, or a hydrochloride saltthereof.

In an exemplary embodiment, the BTK inhibitor is6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-oneor a pharmaceutically acceptable salt thereof, or a hydrochloride saltthereof. The preparation of this compound is described in InternationalPatent Application Publication No. WO 2013/081016 A1.

In an exemplary embodiment, the BTK inhibitor is6-amino-9-[(3S)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-oneor a pharmaceutically acceptable salt thereof, or a hydrochloride saltthereof. The preparation of this compound is described in InternationalPatent Application Publication No. WO 2013/081016 A1.

BTK inhibitors suitable for use in the described combination with a PI3Kinhibitor, the PI3K inhibitor in selected embodiments being selectedfrom the group consisting of a PI3K-γ inhibitor, a PI3K-δ inhibitor, anda PI3K-γ,δ inhibitor also include, but are not limited to, thosedescribed in, for example, International Patent Application PublicationNos. WO 2013/010868; WO 2012/158843; WO 2012/135944; WO 2012/135937;U.S. Patent Application Publication No. 2011/0177011; and U.S. Pat. Nos.8,501,751; 8,476,284; 8,008,309; 7,960,396; 7,825,118; 7,732,454;7,514,444; 7,459,554; 7,405,295; and 7,393,848.

Pharmaceutical Compositions

In one embodiment, the invention provides a pharmaceutical compositioncomprising a combination of a PI3K inhibitor and a BTK inhibitor. Inselected embodiments, the PI3K inhibitor is selected from the groupconsisting of a PI3K-γ inhibitor, a PI3K-δ inhibitor, and a PI3K-γ,δinhibitor. Said pharmaceutical composition typically also comprises atleast one pharmaceutically acceptable excipient.

Said pharmaceutical composition is in one embodiment for use in thetreatment of the diseases and conditions described below. In particular,it is for use in the treatment of hyperproliferative disorders.

In selected embodiments, the invention provides a pharmaceuticalcomposition comprising a combination of a PI3K inhibitor and a BTKinhibitor for treating solid tumor cancers, lymphomas and leukemia. Inselected embodiments, the PI3K inhibitor is selected from the groupconsisting of a PI3K-γ inhibitor, a PI3K-δ inhibitor, and a PI3K-γ,δinhibitor.

In selected embodiments, the invention provides a pharmaceuticalcomposition comprising a combination of a PI3K inhibitor, including aPI3K inhibitor selected from the group consisting of a PI3K-γ, a PI3K-δinhibitor, and a PI3K-γ,δ inhibitor, and a BTK inhibitor for thetreatment of disorders such as hyperproliferative disorder including butnot limited to cancer such as acute myeloid leukemia, thymus, brain,lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma,oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic,bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian,prostate, colorectal, esophageal, testicular, gynecological, thyroid,CNS, PNS, AIDS-related (e.g., lymphoma and Kaposi's sarcoma) orviral-induced cancer. In some embodiments, said pharmaceuticalcomposition is for the treatment of a non-cancerous hyperproliferativedisorder such as benign hyperplasia of the skin (e.g., psoriasis),restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

The invention further provides a pharmaceutical composition comprising acombination of a PI3K inhibitor and a BTK inhibitor for the preventionof blastocyte implantation in a mammal.

The invention also provides a pharmaceutical composition comprising acombination of a PI3K inhibitor and a BTK inhibitor for treating adisease related to vasculogenesis or angiogenesis in a mammal which canmanifest as tumor angiogenesis, chronic inflammatory disease such asrheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skindiseases such as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

The pharmaceutical compositions are typically formulated to provide atherapeutically effective amount of a combination of a PI3K inhibitor,including a PI3K inhibitor selected from the group consisting of aPI3K-γ inhibitor, a PI3K-δ inhibitor, and a PI3K-γ,δ inhibitor, and BTKinhibitor as the active ingredients, or a pharmaceutically acceptablesalt, ester, prodrug, solvate, or hydrate thereof. Where desired, thepharmaceutical compositions contain a pharmaceutically acceptable saltand/or coordination complex thereof, and one or more pharmaceuticallyacceptable excipients, carriers, including inert solid diluents andfillers, diluents, including sterile aqueous solution and variousorganic solvents, permeation enhancers, solubilizers and adjuvants.

The pharmaceutical compositions are administered as a combination of aPI3K inhibitor, including a PI3K inhibitor selected from the groupconsisting of a PI3K-γ inhibitor, a PI3K-δ inhibitor, and a PI3K-γ,δinhibitor, and a BTK inhibitor. Where desired, other agent(s) may bemixed into a preparation or both components may be formulated intoseparate preparations for use in combination separately or at the sametime. A kit containing both components formulated into separatepreparations for said use in also provided by the invention.

The weight ratio of the PI3K inhibitor to the BTK inhibitor in thecombination is typically with the range from 0.01 to 100, preferablyfrom 2.5:1 to 1:2.5, and more preferably about 1:1.

In selected embodiments, the concentration of each of the PI3K and BTKinhibitors provided in the pharmaceutical compositions of the inventionis independently less than, for example, 100%, 90%, 80%, 70%, 60%, 50%,40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%,7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%,0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%,0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%,0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/vor v/v of each of the BTK or PI3K inhibitors.

In selected embodiments, the concentration of each of the PI3K and BTKinhibitors provided in the pharmaceutical compositions of the inventionis independently greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%,17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%,14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%,12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%,9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%,6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%,3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%,1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%,0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v, or v/v of eachof the BTK or PI3K inhibitors.

In selected embodiments, the concentration of each of the PI3K and BTKinhibitors of the invention is independently in the range from about0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% toabout 27%, about 0.05% to about 26%, about 0.06% to about 25%, about0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%,about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% toabout 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9%to about 12% or about 1% to about 10% w/w, w/v or v/v. v/v of each ofthe BTK or PI3K inhibitors.

In selected embodiments, the concentration of each of the PI3K and BTKinhibitors of the invention is independently in the range from about0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%,about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% toabout 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w/w, w/vor v/v of each of the BTK or PI3K inhibitors.

In selected embodiments, the amount of each of the PI3K and BTKinhibitors of the invention is independently equal to or less than 10 g,9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g,4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g,0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g,0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g,0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g or0.0001 g.

In selected embodiments, the amount of each of the PI3K and BTKinhibitors of the invention is independently more than 0.0001 g, 0.0002g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g,0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g,0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g,0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g,0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g,0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g,4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g or 10g.

Each of the PI3K and BTK inhibitors according to the invention iseffective over a wide dosage range. For example, in the treatment ofadult humans, dosages independently range from 0.01 to 1000 mg, from 0.5to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day areexamples of dosages that may be used. The exact dosage will depend uponthe route of administration, the form in which the compound isadministered, the gender and age of the subject to be treated, the bodyweight of the subject to be treated, and the preference and experienceof the attending physician.

Efficacy of the compounds and combinations of compounds described hereinin treating, preventing and/or managing the indicated diseases ordisorders can be tested using various animal models known in the art.Efficacy in treating, preventing and/or managing asthma can be assessedusing the ova induced asthma model described, for example, in Lee etal., J. Allergy Clin. Immunol. 118(2):403-9 (2006). Efficacy intreating, preventing and/or managing arthritis (e.g., rheumatoid orpsoriatic arthritis) can be assessed using the autoimmune animal modelsdescribed in, for example, Williams et al., Chem Biol, 17(2):123-34(2010), WO 2009/088986, WO 2009/088880, and WO 2011/008302. Efficacy intreating, preventing and/or managing psoriasis can be assessed usingtransgenic or knockout mouse model with targeted mutations in epidermis,vasculature or immune cells, mouse model resulting from spontaneousmutations, and immuno-deficient mouse model with xenotransplantation ofhuman skin or immune cells, all of which are described, for example, inBoehncke et al., Clinics in Dermatology, 25: 596-605 (2007). Efficacy intreating, preventing and/or managing fibrosis or fibrotic conditions canbe assessed using the unilateral ureteral obstruction model of renalfibrosis, which is described, for example, in Chevalier et al., KidneyInternational 75:1145-1152 (2009); the bleomycin induced model ofpulmonary fibrosis described in, for example, Moore et al., Am. J.Physiol. Lung. Cell. Mol. Physiol. 294:L152-L160 (2008); a variety ofliver/biliary fibrosis models described in, for example, Chuang et al.,Clin. Liver Dis. 12:333-347 (2008) and Omenetti et al., LaboratoryInvestigation 87:499-514 (2007) (biliary duct-ligated model); or any ofa number of myelofibrosis mouse models such as described in Varicchio etal., Expert Rev. Hematol. 2(3):315-334 (2009). Efficacy in treating,preventing and/or managing scleroderma can be assessed using a mousemodel induced by repeated local injections of bleomycin described, forexample, in Yamamoto et al., J. Invest. Dermatol. 112: 456-462 (1999).Efficacy in treating, preventing and/or managing dermatomyositis can beassessed using a myositis mouse model induced by immunization withrabbit myosin as described, for example, in Phyanagi et al., Arthritis &Rheumatism, 60(10): 3118-3127 (2009). Efficacy in treating, preventingand/or managing lupus can be assessed using various animal modelsdescribed, for example, in Ghoreishi et al., Lupus, 19: 1029-1035(2009); Ohl et al., Journal of Biomedicine and Biotechnology, Article ID432595 (2011); Xia et al., Rheumatology, 50:2187-2196 (2011); Pau etal., PLoS ONE, 7(5):e36761 (2012); Mustafa et al., Toxicology,290:156-168 (2011); Ichikawa et al., Arthritis and Rheumatism, 62(2):493-503 (2012); Ouyang et al., J. Mol. Med. (2012); Rankin et al.,Journal of Immunology,188:1656-1667 (2012). Efficacy in treating,preventing and/or managing Sjögren's syndrome can be assessed usingvarious mouse models described, for example, in Chiorini et al., J.Autoimmunity, 33: 190-196 (2009).

To explore the role of PI3K signaling in diffuse large B-cell lymphoma(“DLBCL”), several DLBCL cell lines of varying molecular profiles may beutilized. In an exemplary embodiment, a cellular growth inhibition assayused five cell lines, including four GCB (SU-DHL-4, SU-DHL-6, OCI-LY-8and WSU-DLCL-2) and one ABC (Ri-1) subtype. In an exemplary embodiment,a cellular growth inhibition assay used five cell lines that wereOCI-LY-3, OCI-LY-7, Pfeiffer, Toledo and U2932. In an exemplaryembodiment, evidence of PI3K pathway inhibition is measured by reductionin phospho (p)-AKT. In an exemplary embodiment, the kinetics of pathwaymodulation was characterized by examination of phosphorylation of AKT,PRAS40 and S6 following a time-course of treatment by a PI3K-inhibitorin selected cell lines. In one embodiment, upon B-cell receptorstimulation via antibody-induced crosslinking, some cell lines exhibitedenhanced AKT phosphorylation.

In an exemplary embodiment, the combination effect of a PI3K inhibitorwith a BTK inhibitor was observed in a cellular growth inhibition assayin the SU-DHL-4 cell line and in the OCI-LY-8 cell line with BCRcrosslinking.

In one embodiment, provided herein is a method of treating, preventingand/or managing asthma. As used herein, “asthma” encompasses airwayconstriction regardless of the cause. Common triggers of asthma include,but are not limited to, exposure to an environmental stimulants (e.g.,allergens), cold air, warm air, perfume, moist air, exercise orexertion, and emotional stress. Also provided herein is a method oftreating, preventing and/or managing one or more symptoms associatedwith asthma. Examples of the symptoms include, but are not limited to,severe coughing, airway constriction and mucus production.

Described below are non-limiting exemplary pharmaceutical compositionsand methods for preparing the same.

Pharmaceutical Compositions for Oral Administration

In selected embodiments, the invention provides a pharmaceuticalcomposition for oral administration containing the combination of a PI3Kand BTK inhibitor, and a pharmaceutical excipient suitable for oraladministration.

In selected embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) an effective amountof each of a PI3K and BTK inhibitor in combination and (ii) apharmaceutical excipient suitable for oral administration. In selectedembodiments, the composition further contains (iii) an effective amountof a fourth compound.

In selected embodiments, the pharmaceutical composition may be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions of the invention suitable for oral administration can bepresented as discrete dosage forms, such as capsules, cachets, ortablets, or liquids or aerosol sprays each containing a predeterminedamount of an active ingredient as a powder or in granules, a solution,or a suspension in an aqueous or non-aqueous liquid, an oil-in-wateremulsion, or a water-in-oil liquid emulsion. Such dosage forms can beprepared by any of the methods of pharmacy, but all methods include thestep of bringing the active ingredient(s) into association with thecarrier, which constitutes one or more necessary ingredients. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active ingredient(s) with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product intothe desired presentation. For example, a tablet can be prepared bycompression or molding, optionally with one or more accessoryingredients. Compressed tablets can be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such aspowder or granules, optionally mixed with an excipient such as, but notlimited to, a binder, a lubricant, an inert diluent, and/or a surfaceactive or dispersing agent. Molded tablets can be made by molding in asuitable machine a mixture of the powdered compound moistened with aninert liquid diluent.

The invention further encompasses anhydrous pharmaceutical compositionsand dosage forms since water can facilitate the degradation of somecompounds. For example, water may be added (e.g., 5%) in thepharmaceutical arts as a means of simulating long-term storage in orderto determine characteristics such as shelf-life or the stability offormulations over time. Anhydrous pharmaceutical compositions and dosageforms of the invention can be prepared using anhydrous or low moisturecontaining ingredients and low moisture or low humidity conditions.Pharmaceutical compositions and dosage forms of the invention whichcontain lactose can be made anhydrous if substantial contact withmoisture and/or humidity during manufacturing, packaging, and/or storageis expected. An anhydrous pharmaceutical composition may be prepared andstored such that its anhydrous nature is maintained. Accordingly,anhydrous compositions may be packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

Each of the PI3K and BTK inhibitors active ingredients can be combinedin an intimate admixture with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier can takea wide variety of forms depending on the form of preparation desired foradministration. In preparing the compositions for an oral dosage form,any of the usual pharmaceutical media can be employed as carriers, suchas, for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents, and the like in the case of oral liquidpreparations (such as suspensions, solutions, and elixirs) or aerosols;or carriers such as starches, sugars, micro-crystalline cellulose,diluents, granulating agents, lubricants, binders, and disintegratingagents can be used in the case of oral solid preparations, in someembodiments without employing the use of lactose. For example, suitablecarriers include powders, capsules, and tablets, with the solid oralpreparations. If desired, tablets can be coated by standard aqueous ornonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the invention toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant may produce tablets whichdisintegrate in the bottle. Too little may be insufficient fordisintegration to occur, thus altering the rate and extent of release ofthe active ingredients from the dosage form. Thus, a sufficient amountof disintegrant that is neither too little nor too much to detrimentallyalter the release of the active ingredient(s) may be used to form thedosage forms of the compounds disclosed herein. The amount ofdisintegrant used may vary based upon the type of formulation and modeof administration, and may be readily discernible to those of ordinaryskill in the art. About 0.5 to about 15 weight percent of disintegrant,or about 1 to about 5 weight percent of disintegrant, may be used in thepharmaceutical composition. Disintegrants that can be used to formpharmaceutical compositions and dosage forms of the invention include,but are not limited to, agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof. Additional lubricants include, for example, a silicagel, a coagulated aerosol of synthetic silica, or mixtures thereof. Alubricant can optionally be added, in an amount of less than about 1weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the essential active ingredient therein may be combinedwith various sweetening or flavoring agents, coloring matter or dyesand, if so desired, emulsifying and/or suspending agents, together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, and mixtures thereof.That is, a mixture of hydrophilic surfactants may be employed, a mixtureof lipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acylactylates; mono- and di-acetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylenesterols, derivatives, and analogues thereof; polyoxyethylated vitaminsand derivatives thereof; polyoxyethylene-polyoxypropylene blockcopolymers; and mixtures thereof; polyethylene glycol sorbitan fattyacid esters and hydrophilic transesterification products of a polyolwith at least one member of the group consisting of triglycerides,vegetable oils, and hydrogenated vegetable oils. The polyol may beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate,sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octylphenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols; oil-solublevitamins/vitamin derivatives; and mixtures thereof. Within this group,preferred lipophilic surfactants include glycerol fatty acid esters,propylene glycol fatty acid esters, and mixtures thereof, or arehydrophobic transesterification products of a polyol with at least onemember of the group consisting of vegetable oils, hydrogenated vegetableoils, and triglycerides.

In an exemplary embodiment, the composition may include a solubilizer toensure good solubilization and/or dissolution of the compound of thepresent invention and to minimize precipitation of the compound of thepresent invention. This can be especially important for compositions fornon-oral use—e.g., compositions for injection. A solubilizer may also beadded to increase the solubility of the hydrophilic drug and/or othercomponents, such as surfactants, or to maintain the composition as astable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, F-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, .epsilon.-caprolactone and isomers thereof,δ-valerolactone and isomers thereof, β-butyrolactone and isomersthereof; and other solubilizers known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin,diethylene glycol monoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. Particularlypreferred solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a patientusing conventional techniques, such as distillation or evaporation.Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%,50%, 100%, or up to about 200% by weight, based on the combined weightof the drug, and other excipients. If desired, very small amounts ofsolubilizer may also be used, such as 5%, 2%, 1% or even less.Typically, the solubilizer may be present in an amount of about 1% toabout 100%, more typically about 5% to about 25% by weight.

The composition can further include one or more pharmaceuticallyacceptable additives and excipients. Such additives and excipientsinclude, without limitation, detackifiers, anti-foaming agents,buffering agents, polymers, antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof.

In addition, an acid or a base may be incorporated into the compositionto facilitate processing, to enhance stability, or for other reasons.Examples of pharmaceutically acceptable bases include amino acids, aminoacid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used. When the base is a salt, the cation can be anyconvenient and pharmaceutically acceptable cation, such as ammonium,alkali metals and alkaline earth metals. Example may include, but notlimited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid and uric acid.

Pharmaceutical Compositions for Injection

In selected embodiments, the invention provides a pharmaceuticalcomposition for injection containing the combination of the PI3K and BTKinhibitors and a pharmaceutical excipient suitable for injection.Components and amounts of agents in the compositions are as describedherein.

The forms in which the compositions of the present invention may beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (andsuitable mixtures thereof), cyclodextrin derivatives, and vegetable oilsmay also be employed. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, for the maintenanceof the required particle size in the case of dispersion and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid and thimerosal.

Sterile injectable solutions are prepared by incorporating thecombination of the PI3K and BTK inhibitors in the required amounts inthe appropriate solvent with various other ingredients as enumeratedabove, as required, followed by filtered sterilization. Generally,dispersions are prepared by incorporating the various sterilized activeingredients into a sterile vehicle which contains the basic dispersionmedium and the required other ingredients from those enumerated above.In the case of sterile powders for the preparation of sterile injectablesolutions, certain desirable methods of preparation are vacuum-dryingand freeze-drying techniques which yield a powder of the activeingredient plus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Pharmaceutical Compositions for Topical Delivery

In some embodiments, the invention provides a pharmaceutical compositionfor transdermal delivery containing the combination of the PI3K and BTKinhibitors and a pharmaceutical excipient suitable for transdermaldelivery.

Compositions of the present invention can be formulated intopreparations in solid, semi-solid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationmay provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the combination of the PI3K and BTK inhibitors in controlledamounts, either with or without another agent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252; 4,992,445 and 5,001,139. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Pharmaceutical Compositions for Inhalation

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

Other Pharmaceutical Compositions

Pharmaceutical compositions may also be prepared from compositionsdescribed herein and one or more pharmaceutically acceptable excipientssuitable for sublingual, buccal, rectal, intraosseous, intraocular,intranasal, epidural, or intraspinal administration. Preparations forsuch pharmaceutical compositions are well-known in the art. See, e.g.,Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds.,Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; andPratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, N.Y., 1990.

Administration of the combination of the PI3K and BTK inhibitors orpharmaceutical composition of these compounds can be effected by anymethod that enables delivery of the compounds to the site of action.These methods include oral routes, intraduodenal routes, parenteralinjection (including intravenous, intraarterial, subcutaneous,intramuscular, intravascular, intraperitoneal or infusion), topical(e.g., transdermal application), rectal administration, via localdelivery by catheter or stent or through inhalation. The combination ofcompounds can also be administered intraadiposally or intrathecally.

The compositions of the invention may also be delivered via animpregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer. Such a method of administrationmay, for example, aid in the prevention or amelioration of restenosisfollowing procedures such as balloon angioplasty. Without being bound bytheory, compounds of the invention may slow or inhibit the migration andproliferation of smooth muscle cells in the arterial wall whichcontribute to restenosis. A compound of the invention may beadministered, for example, by local delivery from the struts of a stent,from a stent graft, from grafts, or from the cover or sheath of a stent.In some embodiments, a compound of the invention is admixed with amatrix. Such a matrix may be a polymeric matrix, and may serve to bondthe compound to the stent. Polymeric matrices suitable for such use,include, for example, lactone-based polyesters or copolyesters such aspolylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides,polyaminoacids, polysaccharides, polyphosphazenes, poly(ether-ester)copolymers (e.g. PEO-PLLA); polydimethylsiloxane,poly(ethylene-vinylacetate), acrylate-based polymers or copolymers(e.g., polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone),fluorinated polymers such as polytetrafluoroethylene and celluloseesters. Suitable matrices may be nondegrading or may degrade with time,releasing the compound or compounds. The combination of the PI3K and BTKinhibitors may be applied to the surface of the stent by various methodssuch as dip/spin coating, spray coating, dip-coating, and/orbrush-coating. The compounds may be applied in a solvent and the solventmay be allowed to evaporate, thus forming a layer of compound onto thestent. Alternatively, the compound may be located in the body of thestent or graft, for example in microchannels or micropores. Whenimplanted, the compound diffuses out of the body of the stent to contactthe arterial wall. Such stents may be prepared by dipping a stentmanufactured to contain such micropores or microchannels into a solutionof the compound of the invention in a suitable solvent, followed byevaporation of the solvent. Excess drug on the surface of the stent maybe removed via an additional brief solvent wash. In yet otherembodiments, compounds of the invention may be covalently linked to astent or graft. A covalent linker may be used which degrades in vivo,leading to the release of the compound of the invention. Any bio-labilelinkage may be used for such a purpose, such as ester, amide oranhydride linkages. The combination of the PI3K and BTK inhibitors mayadditionally be administered intravascularly from a balloon used duringangioplasty. Extravascular administration of the combination of the PI3Kand BTK inhibitors via the pericard or via advential application offormulations of the invention may also be performed to decreaserestenosis.

Exemplary parenteral administration forms include solutions orsuspensions of active compound in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

The invention also provides kits. The kits include each of the PI3K andBTK inhibitors, either alone or in combination in suitable packaging,and written material that can include instructions for use, discussionof clinical studies and listing of side effects. Such kits may alsoinclude information, such as scientific literature references, packageinsert materials, clinical trial results, and/or summaries of these andthe like, which indicate or establish the activities and/or advantagesof the composition, and/or which describe dosing, administration, sideeffects, drug interactions, or other information useful to the healthcare provider. Such information may be based on the results of variousstudies, for example, studies using experimental animals involving invivo models and studies based on human clinical trials. The kit mayfurther contain another agent. In selected embodiments, the PI3K and BTKinhibitors and the agent are provided as separate compositions inseparate containers within the kit. In selected embodiments, the PI3Kand BTK inhibitors and the agent are provided as a single compositionwithin a container in the kit. Suitable packaging and additionalarticles for use (e.g., measuring cup for liquid preparations, foilwrapping to minimize exposure to air, and the like) are known in the artand may be included in the kit. Kits described herein can be provided,marketed and/or promoted to health providers, including physicians,nurses, pharmacists, formulary officials, and the like. Kits may also,in selected embodiments, be marketed directly to the consumer.

Dosages and Dosing Regimens

The amounts of the combination of the PI3K and BTK inhibitorsadministered will be dependent on the mammal being treated, the severityof the disorder or condition, the rate of administration, thedisposition of the compounds and the discretion of the prescribingphysician. However, an effective dosage of a PI3K or a BTK inhibitor isin the range of about 0.001 to about 100 mg per kg body weight per day,such as about 1 to about 35 mg/kg/day, in single or divided doses. For a70 kg human, this would amount to about 0.05 to 7 g/day, such as about0.05 to about 2.5 g/day. In some embodiments, an effective dosage of aBTK inhibitor disclosed herein, either alone or administered incombination with a PI3K inhibitor, is in the range of about 1 mg toabout 300 mg, about 10 mg to about 250 mg, about 20 mg to about 225 mg,about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg toabout 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg,about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg toabout 60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg,about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg toabout 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg,about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mgto about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about198 to about 202 mg. In some embodiments, an effective dosage of a BTKinhibitor disclosed herein, either alone or in combination with a PI3Kinhibitor, is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about250 mg. In some embodiments a BTK inhibitor disclosed herein, isadministered either alone or administered in combination with a PI3Kinhibitor, in a single dose, while in other embodiments a BTK inhibitordisclosed herein, is administered either alone or in combination with aPI3K inhibitor, b.i.d. (twice a day).

In some embodiments, an effective dosage of a BTK inhibitor disclosedherein, either alone or administered in combination with a PI3Kinhibitor, is in the range of about 0.01 mg/kg to about 4.3 mg/kg, about0.15 mg/kg to about 3.6 mg/kg, about 0.3 mg/kg to about 3.2 mg/kg, about0.35 mg/kg to about 2.85 mg/kg, about 0.15 mg/kg to about 2.85 mg/kg,about 0.3 mg to about 2.15 mg/kg, about 0.45 mg/kg to about 1.7 mg/kg,about 0.15 mg/kg to about 1.3 mg/kg, about 0.3 mg/kg to about 1.15mg/kg, about 0.45 mg/kg to about 1 mg/kg, about 0.55 mg/kg to about 0.85mg/kg, about 0.65 mg/kg to about 0.8 mg/kg, about 0.7 mg/kg to about0.75 mg/kg, about 0.7 mg/kg to about 2.15 mg/kg, about 0.85 mg/kg toabout 2 mg/kg, about 1 mg/kg to about 1.85 mg/kg, about 1.15 mg/kg toabout 1.7 mg/kg, about 1.3 mg/kg mg to about 1.6 mg/kg, about 1.35 mg/kgto about 1.5 mg/kg, about 2.15 mg/kg to about 3.6 mg/kg, about 2.3 mg/kgto about 3.4 mg/kg, about 2.4 mg/kg to about 3.3 mg/kg, about 2.6 mg/kgto about 3.15 mg/kg, about 2.7 mg/kg to about 3 mg/kg, about 2.8 mg/kgto about 3 mg/kg, or about 2.85 mg/kg to about 2.95 mg/kg. In someembodiments, an effective dosage of a BTK inhibitor disclosed herein,either alone or administered in combination with a PI3K inhibitor, isabout 0.35 mg/kg, about 0.7 mg/kg, about 1 mg/kg, about 1.4 mg/kg, about1.8 mg/kg, about 2.1 mg/kg, about 2.5 mg/kg, about 2.85 mg/kg, about 3.2mg/kg, or about 3.6 mg/kg. In some embodiments a BTK inhibitor disclosedherein, is administered either alone or in combination with a PI3Kinhibitor, in a single dose, while in other embodiments a BTK inhibitordisclosed herein, is administered either alone or in combination with aPI3K inhibitor, b.i.d. (twice a day).

In some embodiments, an effective dosage of a PI3K inhibitor disclosedherein, either alone or administered in combination with a BTKinhibitor, is in the range of about 1 mg to about 300 mg, about 10 mg toabout 250 mg, about 20 mg to about 225 mg, about 25 mg to about 200 mg,about 1 mg to about 50 mg, about 5 mg to about 45 mg, about 10 mg toabout 40 mg, about 15 mg to about 35 mg, about 20 mg to about 30 mg,about 23 mg to about 28 mg, about 50 mg to about 150 mg, about 60 mg toabout 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg,about 90 mg to about 110 mg, or about 95 mg to about 105 mg, about 98 mgto about 102 mg, about 150 mg to about 250 mg, about 160 mg to about 240mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 toabout 207 mg. In some embodiments, an effective dosage of a PI3Kinhibitor disclosed herein, either alone or administered in combinationwith a BTK inhibitor, is about 25 mg, about 50 mg, about 75 mg, about100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about225 mg, or about 250 mg. In some embodiments the PI3K inhibitordisclosed herein, is administered either alone or in combination with aBTK inhibitor, in a single dose, while in other embodiments a PI3Kinhibitor disclosed herein, is administered either alone or incombination with a BTK inhibitor, b.i.d. (twice a day).

In some embodiments, an effective dosage of a PI3K inhibitor disclosedherein, either alone or administered in combination with a BTKinhibitor, is in the range of about 0.01 mg/kg to about 4.3 mg/kg, about0.15 mg/kg to about 3.6 mg/kg, about 0.3 mg/kg to about 3.2 mg/kg, about0.35 mg/kg to about 2.85 mg/kg, about 0.01 mg/kg to about 0.7 mg/kg,about 0.07 mg/kg to about 0.65 mg/kg, about 0.15 mg/kg to about 0.6mg/kg, about 0.2 mg/kg to about 0.5 mg/kg, about 0.3 mg/kg to about 0.45mg/kg, about 0.3 mg/kg to about 0.4 mg/kg, about 0.7 mg/kg to about 2.15mg/kg, about 0.85 mg/kg to about 2 mg/kg, about 1 mg/kg to about 1.85mg/kg, about 1.15 mg/kg to about 1.7 mg/kg, about 1.3 mg/kg to about 1.6mg/kg, about 1.35 mg/kg to about 1.5 mg/kg, about 1.4 mg/kg to about1.45 mg/kg, about 2.15 mg/kg to about 3.6 mg/kg, about 2.3 mg/kg toabout 3.4 mg/kg, about 2.4 mg/kg to about 3.3 mg/kg, about 2.6 mg/kg toabout 3.15 mg/kg, about 2.7 mg/kg to about 3 mg/kg, about 2.8 mg/kg toabout 3 mg/kg, or about 2.85 mg/kg to about 2.95 mg/kg. In someembodiments, an effective dosage of a PI3K inhibitor disclosed herein,either alone or administered in combination with a BTK inhibitor, isabout 0.4 mg/kg, about 0.7 mg/kg, about 1 mg/kg, about 1.4 mg/kg, about1.8 mg/kg, about 2.1 mg/kg, about 2.5 mg/kg, about 2.85 mg/kg, about 3.2mg/kg, or about 3.6 mg/kg. In some embodiments a PI3K inhibitordisclosed herein, is administered either alone or in combination with aBTK inhibitor, in a single dose, while in other embodiments a PI3Kinhibitor disclosed herein, is administered either alone or incombination with a BTK inhibitor, b.i.d. (twice a day).

In some embodiments, 10 to 200 mg BID including 50, 60, 70, 80, 90, 100or 150 mg BID, for the BTK inhibitor, and 10 to 300 mg BID including 25,50, 75, 100, 150 or 200 mg BID for the PI3K inhibitor. In someinstances, dosage levels below the lower limit of the aforesaid rangemay be more than adequate, while in other cases still larger doses maybe employed without causing any harmful side effect—e.g., by dividingsuch larger doses into several small doses for administration throughoutthe day.

In selected embodiments, the combination of the PI3K and BTK inhibitorsis administered in a single dose. In selected embodiments, suchadministration will be by injection—e.g., intravenous injection, inorder to introduce the agents quickly. However, other routes may be usedas appropriate. A single dose of the combination of the PI3K and BTKinhibitors may also be used for treatment of an acute condition.

In selected embodiments, the combination of the PI3K and BTK inhibitorsis administered in multiple doses. Dosing may be about once, twice,three times, four times, five times, six times, or more than six timesper day. Dosing may be about once a month, once every two weeks, once aweek, or once every other day. In other embodiments, the combination ofthe PI3K and BTK inhibitors is administered about once per day to about6 times per day. In another embodiment the administration of thecombination of the PI3K and BTK inhibitors continues for less than about7 days. In yet another embodiment the administration continues for morethan about 6, 10, 14, 28 days, two months, six months, or one year. Insome cases, continuous dosing is achieved and maintained as long asnecessary.

Administration of the agents of the invention may continue as long asnecessary. In selected embodiments, the combination of the PI3K and BTKinhibitors is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28days. In some embodiments, the combination of the PI3K and BTKinhibitors is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1day. In selected embodiments, the combination of the PI3K and BTKinhibitors is administered chronically on an ongoing basis—e.g., for thetreatment of chronic effects.

An effective amount of the combination of the PI3K and BTK inhibitorsmay be administered in either single or multiple doses by any of theaccepted modes of administration of agents having similar utilities,including rectal, buccal, intranasal and transdermal routes, byintra-arterial injection, intravenously, intraperitoneally,parenterally, intramuscularly, subcutaneously, orally, topically, or asan inhalant.

Methods of Treatment

In selected embodiments, the invention provides a method of treating ahyperproliferative disorder in a mammal that comprises administering tosaid mammal a therapeutically effective amount of a PI3K inhibitor (or aPI3K-γ inhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) and BTKinhibitor, or a pharmaceutically acceptable salt or ester, prodrug,solvate or hydrate of either or both the PI3K inhibitor (or a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) or the BTKinhibitor. In selected embodiments, the method relates to the treatmentof cancer such as non-Hodgkin's lymphomas (such as diffuse large B-celllymphoma), acute myeloid leukemia, thymus, brain, lung, squamous cell,skin, eye, retinoblastoma, intraocular melanoma, oral cavity andoropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast,cervical, head, neck, renal, kidney, liver, ovarian, prostate,colorectal, bone (e.g., metastatic bone), esophageal, testicular,gynecological, thyroid, CNS, PNS, AIDS-related (e.g. lymphoma andKaposi's sarcoma), viral-induced cancers such as cervical carcinoma(human papillomavirus), B-cell lymphoproliferative disease andnasopharyngeal carcinoma (Epstein-Barr virus), Kaposi's Sarcoma andprimary effusion lymphomas (Kaposi's sarcoma herpesvirus),hepatocellular carcinoma (hepatitis B and hepatitis C viruses), andT-cell leukemias (Human T-cell leukemia virus-1), and T-cell leukemias(Human T-cell leukemia virus-1), B cell acute lymphoblastic leukemia,Burkitt's leukemia, juvenile myelomonocytic leukemia, hairy cellleukemia, Hodgkin's disease, multiple myeloma, mast cell leukemia, ormastocytosis. In selected embodiments, the method relates to thetreatment of a non-cancerous hyperproliferative disorder such as benignhyperplasia of the skin (e.g., psoriasis), restenosis, or prostateconditions (e.g., benign prostatic hypertrophy (BPH)).

In selected embodiments, the invention provides a method of treating aninflammatory, immune, or autoimmune disorder in a mammal that comprisesadministering to said mammal a therapeutically effective amount of aPI3K inhibitor (or a PI3K-γ inhibitor, PI3K-δ inhibitor, or PI3K-γ,δinhibitor) and BTK inhibitor, or a pharmaceutically acceptable salt orester, prodrug, solvate or hydrate of either or both the PI3K inhibitor(or a PI3K-γ inhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) or theBTK inhibitor. In selected embodiments, the invention also provides amethod of treating a disease selected from the group consisting of tumorangiogenesis, chronic inflammatory disease, rheumatoid arthritis,atherosclerosis, inflammatory bowel disease, skin diseases such aspsoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma and melanoma, ulcerative colitis, atopic dermatitis,pouchitis, spondylarthritis, uveitis, Behcets disease, polymyalgiarheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease,juvenile idiopathic arthritis, hidratenitis suppurativa, Sjögren'ssyndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosingspondylitis, Crohn's Disease, lupus, and lupus nephritis.

In selected embodiments, the invention provides a method of treating asolid tumor cancer with a composition including a combination of a PI3Kinhibitor, including a PI3K-γ or PI3K-δ inhibitor, and a BTK inhibitor,wherein the dose is effective to inhibit signaling between the solidtumor cells and at least one microenvironment selected from the groupconsisting of macrophages, monocytes, mast cells, helper T cells,cytotoxic T cells, regulatory T cells, natural killer cells,myeloid-derived suppressor cells, regulatory B cells, neutrophils,dendritic cells, and fibroblasts. In selected embodiments, the inventionprovides a method of treating pancreatic cancer, breast cancer, ovariancancer, melanoma, lung cancer, head and neck cancer, and colorectalcancer using a combination of a BTK inhibitor and a PI3K inhibitor,wherein the dose is effective to inhibit signaling between the solidtumor cells and at least one microenvironment selected from the groupconsisting of macrophages, monocytes, mast cells, helper T cells,cytotoxic T cells, regulatory T cells, natural killer cells,myeloid-derived suppressor cells, regulatory B cells, neutrophils,dendritic cells, and fibroblasts. Efficacy of the compounds andcombinations of compounds described herein in treating, preventingand/or managing the indicated diseases or disorders can be tested usingvarious models known in the art. For example, models for determiningefficacy of treatments for pancreatic cancer are described inHerreros-Villanueva, et al. World J. Gastroenterol. 2012, 18, 1286-1294.Models for determining efficacy of treatments for breast cancer aredescribed e.g. in A. Fantozzi, Breast Cancer Res. 2006, 8, 212. Modelsfor determining efficacy of treatments for ovarian cancer are describede.g. in Mullany et al., Endocrinology 2012, 153, 1585-92; and Fong etal., J. Ovarian Res. 2009, 2, 12. Models for determining efficacy oftreatments for melanoma are described e.g. in Damsky et al., PigmentCell & Melanoma Res. 2010, 23, 853-859. Models for determining efficacyof treatments for lung cancer are described e.g. in Meuwissen et al.,Genes & Development, 2005, 19, 643-664. Models for determining efficacyof treatments for lung cancer are described e.g. in Kim, Clin. Exp.Otorhinolaryngol. 2009, 2, 55-60; and Sano, Head Neck Oncol. 2009, 1,32. Models for determining efficacy of treatments for colorectal cancer,including the CT26 model, are described below in the examples.

Efficacy of the compounds and combinations of compounds described hereinin treating, preventing and/or managing other indicated diseases ordisorders described here can also be tested using various models knownin the art. Efficacy in treating, preventing and/or managing asthma canbe assessed using the ova induced asthma model described, for example,in Lee et al., J. Allergy Clin. Immunol. 2006, 118, 403-9. Efficacy intreating, preventing and/or managing arthritis (e.g., rheumatoid orpsoriatic arthritis) can be assessed using the autoimmune animal modelsdescribed in, for example, Williams et al., Chem. Biol. 2010, 17,123-34, WO 2009/088986, WO 2009/088880, and WO 2011/008302. Efficacy intreating, preventing and/or managing psoriasis can be assessed usingtransgenic or knockout mouse model with targeted mutations in epidermis,vasculature or immune cells, mouse model resulting from spontaneousmutations, and immuno-deficient mouse model with xenotransplantation ofhuman skin or immune cells, all of which are described, for example, inBoehncke et al., Clinics in Dermatology, 2007, 25, 596-605. Efficacy intreating, preventing and/or managing fibrosis or fibrotic conditions canbe assessed using the unilateral ureteral obstruction model of renalfibrosis, which is described, for example, in Chevalier et al., KidneyInternational 2009, 75, 1145-1152; the bleomycin induced model ofpulmonary fibrosis described in, for example, Moore et al., Am. J.Physiol. Lung. Cell. Mol. Physiol. 2008, 294, L152-L160; a variety ofliver/biliary fibrosis models described in, for example, Chuang et al.,Clin. Liver Dis. 2008, 12, 333-347 and Omenetti et al., LaboratoryInvestigation, 2007, 87, 499-514 (biliary duct-ligated model); or any ofa number of myelofibrosis mouse models such as described in Varicchio etal., Expert Rev. Hematol. 2009, 2, 315-334. Efficacy in treating,preventing and/or managing scleroderma can be assessed using a mousemodel induced by repeated local injections of bleomycin described, forexample, in Yamamoto et al., J. Invest. Dermatol. 1999, 112, 456-462.Efficacy in treating, preventing and/or managing dermatomyositis can beassessed using a myositis mouse model induced by immunization withrabbit myosin as described, for example, in Phyanagi et al., Arthritis &Rheumatism, 2009, 60(10), 3118-3127. Efficacy in treating, preventingand/or managing lupus can be assessed using various animal modelsdescribed, for example, in Ghoreishi et al., Lupus, 2009, 19, 1029-1035;Ohl et al., J. Biomed. & Biotechnol., Article ID 432595 (2011); Xia etal., Rheumatology, 2011, 50, 2187-2196; Pau et al., PLoS ONE, 2012,7(5), e36761; Mustafa et al., Toxicology, 2011, 90, 156-168; Ichikawa etal., Arthritis & Rheumatism, 2012, 62(2), 493-503; Rankin et al., J.Immunology, 2012, 188, 1656-1667. Efficacy in treating, preventingand/or managing Sjögren's syndrome can be assessed using various mousemodels described, for example, in Chiorini et al., J. Autoimmunity,2009, 33, 190-196.

In selected embodiments, the invention provides a method of treating acancer in a human sensitive to platelet-mediated thrombosis, comprisingthe step of administering a therapeutically effective dose of a BTKinhibitor, or a pharmaceutically-acceptable salt, cocrystal, hydrate,solvate, or prodrug thereof. In a preferred embodiment, the inventionprovides a method of treating a cancer in a human sensitive toplatelet-mediated thrombosis, comprising the step of administering atherapeutically effective dose of a BTK inhibitor, wherein the BTKinhibitor is Formula (XVIII), or a pharmaceutically-acceptable salt,cocrystal, hydrate, solvate, or prodrug thereof. In a preferredembodiment, the invention provides a method of treating a cancer in ahuman sensitive to platelet-mediated thrombosis, comprising the step ofadministering a therapeutically effective dose of a BTK inhibitor,wherein the BTK inhibitor is Formula (XVIII), or apharmaceutically-acceptable salt, cocrystal, hydrate, solvate, orprodrug thereof, further comprising the step of administering atherapeutically effective dose of an anticoagulent or antiplateletagent.

In a preferred embodiment, the invention provides a method of treating acancer in a human sensitive to platelet-mediated thrombosis, comprisingthe step of administering a therapeutically effective dose of a BTKinhibitor, wherein the BTK inhibitor is Formula (XVIII), or apharmaceutically-acceptable salt, cocrystal, hydrate, solvate, orprodrug thereof, further comprising the step of administering atherapeutically effective dose of an anticoagulent or antiplateletagent, wherein the anticoagulent or antiplatelet agent is selected fromthe group consisting of clopidogrel, prasugrel, ticagrelor, ticlopidine,warfarin, acenocoumarol, dicumarol, phenprocoumon, heparain, lowmolecular weight heparin, fondaparinux, and idraparinux.

In selected embodiments, the invention provides a method of treating acancer in a human sensitive to platelet-mediated thrombosis, comprisingthe step of administering a therapeutically effective dose of a BTKinhibitor, wherein the BTK inhibitor is Formula (XVIII), and wherein thecancer is selected from the group consisting of bladder cancer, squamouscell carcinoma including head and neck cancer, pancreatic ductaladenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammarycarcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cellcarcinoma, lung carcinoma, thyoma, prostate cancer, colorectal cancer,ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer,squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma,intraocular melanoma, oral cavity and oropharyngeal cancers, gastriccancer, stomach cancer, cervical cancer, head, neck, renal cancer,kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectalcancer, esophageal cancer, testicular cancer, gynecological cancer,thyroid cancer, aquired immune deficiency syndrome (AIDS)-relatedcancers (e.g., lymphoma and Kaposi's sarcoma), viral-induced cancer,glioblastoma, esophogeal tumors, hematological neoplasms, non-small-celllung cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma,esophagus tumor, follicle center lymphoma, head and neck tumor,hepatitis C virus infection, hepatocellular carcinoma, Hodgkin'sdisease, metastatic colon cancer, multiple myeloma, non-Hodgkin'slymphoma, indolent non-Hogkin's lymphoma, ovary tumor, pancreas tumor,renal cell carcinoma, small-cell lung cancer, stage IV melanoma, chroniclymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), matureB-cell ALL, follicular lymphoma, mantle cell lymphoma, and Burkitt'slymphoma.

In selected embodiments, the invention provides a method of treating acancer in a human with a history of thrombosis, comprising the step ofadministering a therapeutically effective dose of a BTK inhibitor, or apharmaceutically-acceptable salt, cocrystal, hydrate, solvate, orprodrug thereof. In selected embodiments, the invention provides amethod of treating a cancer in a human sensitive to platelet-mediatedthrombosis, method of treating a cancer in a human with a history ofthrombosis, comprising the step of administering a therapeuticallyeffective dose of a BTK inhibitor, wherein the BTK inhibitor is acompound of Formula (XVIII) or a pharmaceutically-acceptable salt,cocrystal, hydrate, solvate, or prodrug thereof.

In selected embodiments, the BTK inhibitor and the anticoagulent or theantiplatelet agent are administered sequentially. In selectedembodiments, the BTK inhibitor and the anticoagulent or the antiplateletagent are administered concomittently. In selected embodiments, the BTKinhibitor is administered before the anticoagulent or the antiplateletagent. In selected embodiments, the BTK inhibitor is administered afterthe anticoagulent or the antiplatelet agent.

Preferred anti-platelet and anticoagulent agents for use in the methodsof the present invention include, but are not limited to, cyclooxygenaseinhibitors (e.g., aspirin), adenosine diphosphate (ADP) receptorinhibitors (e.g., clopidogrel and ticlopidine), phosphodiesteraseinhibitors (e.g., cilostazol), glycoprotein IIb/IIIa inhibitors (e.g.,abciximab, eptifibatide, and tirofiban), adenosine reuptake inhibitors(e.g., dipyridamole), and acetylsalicylic acid (aspirin). In otherembodiments, examples of anti-platelet agents for use in the methods ofthe present invention include anagrelide, aspirin/extended-releasedipyridamole, cilostazol, clopidogrel, dipyridamole, prasugrel,ticagrelor, ticlopidine, vorapaxar, tirofiban HCl, eptifibatide,abciximab, argatroban, bivalirudin, dalteparin, desirudin, enoxaparin,fondaparinux, heparin, lepirudin, apixaban, dabigatran etexilatemesylate, rivaroxaban, and warfarin.

Combinations of PI3K and BTK Inhibitors

Non-limiting, exemplary embodiments of combinations of the PI3Kinhibitors and BTK inhibitors described above are given in the followingnumbered paragraphs 1 to 50. The disclosure encompassed herein should inno way be construed as being limited to these examples, but rathershould be construed to encompass any and all variations which becomeevident as a result of the teachings provided herein.

In an embodiment, the PI3K inhibitor and BTK inhibitor are provided in aPI3K inhibitor to BTK inhibitor ratio (by mass) selected from the groupconsisting of 0.01 to 1, 0.05 to 1, 0.1 to 1, 0.5 to 1, 1 to 1, 2 to 1,5 to 1, 10 to 1, 20 to 1, and 100 to 1.

While preferred embodiments of the invention are shown and describedherein, including the above embodiments, such embodiments are providedby way of example only and are not intended to otherwise limit the scopeof the invention. Various alternatives to the described embodiments ofthe invention may be employed in practicing the invention.

EXAMPLES

The embodiments encompassed herein are now described with reference tothe following examples. These examples are provided for the purpose ofillustration only and the disclosure encompassed herein should in no waybe construed as being limited to these examples, but rather should beconstrued to encompass any and all variations which become evident as aresult of the teachings provided herein.

Example 1—Synergistic Combination of a BTK Inhibitor and a PI3K-δInhibitor

Ficoll purified mantle cell lymphoma (MCL) cells (2×10⁵) isolated frombone marrow or peripheral blood were treated with each drug alone andwith six equimolar concentrations of a BTK inhibitor (Formula XVIII) anda PI3K-δ inhibitor (Formula IX) ranging from 0.01 nM to 10 M on 96-wellplates in triplicate. Plated cells were then cultured in HS-5conditioned media at 37° C. with 5% CO₂. After 72 hours of culture, cellviability was determined using an(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)(MTS) assay (Cell Titer 96, Promega). Viability data were used togenerate cell viability curves for each drug alone and in combinationfor each sample. The potential synergy of the combination of the BTKinhibitor of Formula XVIII and the PI3K-δ inhibitor of Formula IX at agiven equimolar concentration was determined using the median effectmodel as described in Chou and Talalay, Adv Enzyme Regul. 1984, 22,27-55. The statistical modeling was run in R using a script thatutilizes the median effect model as described in Lee et al., J.Biopharm. Stat. 2007, 17, 461-80. A value of 1, less than 1, and greaterthan 1 using R defines an additive interaction, synergistic andantagonistic, respectively. The Lee et al. method calculates a 95%confidence interval for each data point. For each viability curve, to beconsidered synergistic, a data point must have an interaction indexbelow 1 and the upper confidence interval must also be below 1. In orderto summarize and demonstrate collective synergy results, an interactiondot blot was generated for the primary patient samples.

A similar approach was utilized to study diffuse large B cell lymphoma(DLBCL) (TMD8) and MCL (MINO) cell lines. Cells were treated with eachdrug alone and with six equimolar concentrations of the BTK inhibitor ofFormula XVIII and the PI3K-δ inhibitor of Formula IX ranging from 0.003nM to 1.0 μM (for TMD8) or 0.03 nM to 10 μM (for MINO) on 96-well platesin triplicate. Plated cells were then cultured in standard conditionedmedia plus FBS at 37° C. with 5% CO₂. After 72 hours of culture,viability was determined using an MTS assay (Cell Titer 96, Promega).Viability data were used to generate cell viability curves for each drugalone and in combination for each sample. The results of the experimentsdescribed in this example are shown in FIG. 1, FIG. 2, FIG. 3, and FIG.4.

Example 2—Synergistic Combination of a BTK Inhibitor and a PI3K-δInhibitor

Combination experiments were performed to determine the synergistic,additive, or antagonistic behavior of drug combinations using theChou/Talalay method/algorithm by defining combination indexes for drugcombinations. Information about experimental design for evaluation ofsynergy is described in e.g. Chou and Talalay, Adv. Enzyme Regul. 1984,22, 27-55 and more generally in e.g. Greco et al., Pharmacol. Rev. 1995,47, 331-385. The study was performed using the BTK inhibitor of Formula(XVIII) and the PI3K-δ inhibitor of Formula (IX). Single agentactivities were first determined in the various cell lines andsubsequently, the combination indexes were established using equimolarratios taking the single agent drug EC50s into consideration. Forindividual agents that displayed no single agent activity, equimolarratios were used at fixed concentrations to establish combinationindexes. The readout from 72 hour proliferation assays using CellTiterGlo (ATP content of remaining cells) determined the fraction ofcells that were effected as compared to untreated cells (Fa=fractionaffected=(1−((cells+inhibitor)−backgroundsignal)/((cells+DMSO)−background signal)).

The combination index obtained was ranked according to Table 1.

TABLE 1 Combination Index (CI) Ranking Scheme Range of CI Description  <0.1 Very strong synergism 0.1-0.3 Strong synergism 0.3-0.7 Synergism 0.7-0.85 Moderate synergism 0.85-0.9  Slight synergism 0.9-1.1 Nearlyadditive 1.1-1.2 Slight antagonism  1.2-1.45 Moderate antagonism1.45-3.3  Antagonism 3.3-10  Strong antagonism >10 Very strongantagonism

The detailed results of the cell line studies for the BTK inhibitor ofFormula (XVIII) and the PI3K-δ inhibitor of Formula (IX) are given inFIG. 5 to FIG. 37. The results of the cell line studies are summarizedin Table 2.

TABLE 2 Summary of results of the combination of a BTK inhibitor with aPI3K-δ inhibitor (S = synergistic, A = additive, X = no effect). CellLine Indication ED25 ED50 ED75 ED90 Raji Burkitt's S S S S RamosBurkitt's X X X X Daudi Burkitt's S S S S Mino MCL S S S S Pfeiffer iNHLS S S S DOHH iNHL S S S S REC-1 iNHL S S A A U937 Myeloid S S S S K562CML X X X X SU-DHL-1 ABC S A X X SU-DHL-2 ABC S S S S HBL-1 ABC S S S STMD8 ABC S S S S LY19 GCB X X X X LY7 GCB S S S S LY1 GCB X X X XSU-DHL-6 GCB S S S S SupB15 B-ALL S S S S CCRF B-ALL S A/S X X

Example 3—BTK Inhibitory Effects on Solid Tumor Microenvironment in anOrthotopic Pancreatic Cancer Model

An orthotopic pancreatic cancer model was used to investigate thetherapeutic efficacy of the combination of the BTK inhibitor of Formula(XVIII) and the PI3K-δ inhibitor of Formula (IX) through treatment ofthe solid tumor microenvironment. Mice were dosed orally with 15 mg/kgof Formula (XVIII), 15 mg/kg of Formula (IX), or a combination of 15mg/kg of both drugs.

Cell line derived from KrasGl2D; Trp53R172H; Pdx1-Cre (KPC) mice wereorthotopically implanted into the head of the pancreas after 35passages. Based on the mice background from where the cell lines weregenerated, 1×10⁶ cells were injected in C57BL/6 mice. Throughout theexperiment, animals were provided with food and water ad libitum andsubjected to a 12-h dark/light cycle. Animal studies were performed inaccordance with the U.S. Public Health Service “Guidelines for the Careand Use of Laboratory Animals” (IACUC). After euthanization, pancreatictumors were dissected out, weighed and single cell suspensions wereprepared for flow cytometry analysis.

Results of the experiments are shown in FIG. 38, which illustrates tumorgrowth suppression in the orthotopic pancreatic cancer model. Thestatistical p-value (presumption against null hypothesis) is shown foreach tested single agent and for the combination against the vehicle.The results show that all three treatments provide statisticallysignificant reductions in tumor volume in the pancreatic cancer model.

Additional results of the experiments relating to treatment of the tumormicroenvironment are shown in FIG. 39 to FIG. 41. FIG. 39 shows theeffects of oral dosing with 15 mg/kg of the BTK inhibitor of Formula(XVIII), 15 mg/kg of the PI3K inhibitor of Formula (IX), or acombination of both drugs on myeloid tumor-associated macrophages (TAMs)in pancreatic tumor-bearing mice. FIG. 40 illustrates the effects oforal dosing with 15 mg/kg of the BTK inhibitor of Formula (XVIII), 15mg/kg of the PI3K inhibitor of Formula (IX), or a combination of bothinhibitors on myeloid-derived suppressor cells (MDSCs) in pancreatictumor-bearing mice. FIG. 41 illustrates the effects of oral dosing with15 mg/kg of the BTK inhibitor of Formula (XVIII), 15 mg/kg of the PI3Kinhibitor of Formula (IX), or a combination of both inhibitors onregulatory T cells (Tregs) in pancreatic tumor-bearing mice. The resultsshown in FIG. 39 to FIG. 41 demonstrate that administration of the BTKinhibitor of Formula (XVIII) and the combination of the BTK inhibitor ofFormula (XVIII) and the PI3K inhibitor of Formula (IX) reduceimmunosuppressive tumor associated myeloid cells and Tregs in pancreatictumor-bearing mice. Overall, BTK inhibition with Formula (XVIII) or acombination of Formula (XVIII) and Formula (IX) significantly reducedtumor burden in an aggressive orthotopic PDA model, decreased immaturemyeloid infiltrate, reduced the number of tumor associated macrophages,and reduced the number of immunosuppressive Tregs, demonstrating astrong effect on the tumor microenvironment.

Example 4—BTK Inhibitory Effects on Solid Tumor Microenvironment in anOvarian Cancer Model

The ID8 syngeneic orthotropic ovarian cancer murine model was used toinvestigate the therapeutic efficacy of the BTK inhibitor of Formula(XVIII) through treatment of the solid tumor microenvironment. Humanovarian cancer models, including the ID8 syngeneic orthotropic ovariancancer model and other animal models, are described in Fong and Kakar,J. Ovarian Res. 2009, 2, 12; Greenaway et al., Gynecol. Oncol. 2008,108, 385-94; Urzua et al., Tumour Biol. 2005, 26, 236-44; Janat-Amsburyet al., Anticancer Res. 2006, 26, 3223-28; Janat-Amsbury et al.,Anticancer Res. 2006, 26, 2785-89. Animals were treated with vehicle orFormula (XVIII), 15 mg/kg/BID given orally. The results of the study areshown in FIG. 42, FIG. 43, FIG. 44, FIG. 45, FIG. 46, FIG. 47, FIG. 48,and FIG. 49.

FIG. 42 and FIG. 43 demonstrate that the BTK inhibitor of Formula(XVIII) impairs ID8 ovarian cancer growth in the ID8 syngeneic murinemodel. FIG. 44 shows that tumor response to treatment with the BTKinhibitor of Formula (XVIII) correlates with a significant reduction inimmunosuppressive tumor-associated lymphocytes in tumor-bearing mice.FIG. 45 shows treatment with the BTK inhibitor of Formula (XVIII)impairs ID8 ovarian cancer growth (through reduction in tumor volume) inthe syngeneic murine model. FIG. 46 and FIG. 47 show that the tumorresponse induced by treatment with the BTK inhibitor of Formula (XVIII)correlates with a significant reduction in immunosuppressive B cells intumor-bearing mice. FIG. 48 and FIG. 49 show that the tumor responseinduced by treatment with the BTK inhibitor of Formula (XVIII)correlates with a significant reduction in immunosuppressive tumorassociated Tregs and an increase in CD8⁺ T cells.

The results shown in FIG. 42 to FIG. 49 illustrate the surprisingefficacy of the BTK inhibitor of Formula (XVIII) in modulating tumormicroenvironment in a model predictive of efficacy as a treatment forovarian cancer in humans.

Example 5—BTK Inhibitory Effects on Solid Tumor Microenvironment ThroughModulation of Tumor-Infiltrating MDSCs and TAMs

A study was performed to observe potential reduction in tumor burdenthrough modulation of tumor infiltrating MDSCs and TAMs using the BTKinhibitor of Formula (XVIII) and/or gemcitabine (“Gem”). In this study,KPC derived mouse pancreatic cancer cells (KrasGl2D; Trp53R172H;Pdx1-Cre) were injected into the pancreases. Animals were treated with(1) vehicle; (2) Formula (XVIII), 15 mg/kg/BID given orally; (3)gemcitabine 15 mg/kg intravenous (IV) administered every 4 days for 3injections; or (4) Formula (XVIII), 15 mg/kg/BID given orally withtogether with gemcitabine, 15 mg/kg IV administered every 4 days for 3injections.

Single cell suspensions from tumor samples. Mouse tumor tissue wascollected and stored in PBS/0.1% soybean trypsin inhibitor prior toenzymatic dissociation. Samples were finely minced with a scissors andmouse tissue was transferred into DMEM containing 1.0 mg/ml collagenaseIV (Gibco), 0.1% soybean trypsin inhibitor, and 50 U/ml DNase (Roche)and incubated at 37C for 30 min. with constant stirring while humantissue was digested in 2.0 mg/ml collagenase IV, 1.0 mg/ml hyluronidase,0.1% soybean trypsin inhibitor, and 50 U/ml DNase for 45 minutes.Suspensions were filtered through a 100 micron filter and washed withFACS buffer (PBS/0.5% BSA/2.0 mM EDTA) prior to staining. Two milliontotal cells were stained with antibodies as indicated. Intracellulardetection of FoxP3 was achieved following permeabilization with BD PermBuffer III (BD Biosciences) and eBioscience Fix/Perm respectively.Following surface staining, samples were acquired on a BD Fortessa andanalyzed using FlowJo (Treestar) software.

In FIG. 50, the reduction in tumor size upon treatment is shown. Theeffects on particular cell subsets are shown in the flow cytometry datapresented in FIG. 51, FIG. 52, FIG. 53, and FIG. 54.

The results shown in FIG. 50 to FIG. 54 illustrate reduction in tumorburden by modulating the tumor infiltrating MDSCs and TAMs, whichaffects Treg and CD8⁺ T cell levels, through inhibition of BTK usingFormula (XVIII).

Example 6—Effects of BTK Inhibitors on Thrombosis

Clinical studies have shown that targeting the BCR signaling pathway byinhibiting BTK produces significant clinical benefit (Byrd, et al., N.Engl. J. Med. 2013, 369(1), 32-42, Wang, et al., N. Engl. J. Med. 2013,369(6), 507-16). However, in these studies, bleeding has been reportedin up to 50% of ibrutinib-treated patients. Most bleeding events were ofgrade 1-2 (spontaneous bruising or petechiae) but, in 5% of patients,they were of grade 3 or higher after trauma. These results are reflectedin the prescribing information for ibrutinib, where bleeding events ofany grade, including bruising and petechiae, were reported inapproximately half of patients treated with ibrutinib (IMBRUVICA packageinsert and prescribing information, revised July 2014, U.S. Food andDrug Administration).

Constitutive or aberrant activation of the BCR signaling cascade hasbeen implicated in the propagation and maintenance of a variety of Bcell malignancies. Small molecule inhibitors of BTK, a protein early inthis cascade and specifically expressed in B cells, have emerged as anew class of targeted agents. There are several BTK inhibitors,including Formula XXVII (CC-292), and Formula XX-A (PCI-32765,ibrutinib), in clinical development. Importantly, early stage clinicaltrials have found ibrutinib to be particularly active in chroniclymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), suggestingthat this class of inhibitors may play a significant role in varioustypes of cancers (Aalipour and Advani, Br. J. Haematol. 2013, 163,436-43). However, their effects are not limited to leukemia or lymphomasas platelets also rely on the Tec kinases family members BTK and Tec forsignal transduction in response to various thrombogenic stimuli (Oda, etal., Blood 2000, 95(5), 1663-70; Atkinson, et al. Blood 2003, 102(10),3592-99). In fact, both Tec and BTK play an important role in theregulation of phospholipase Cγ2 (PLCγ2) downstream of the collagenreceptor glycoprotein VI (GPVI) in human platelets. In addition, BTK isactivated and undergoes tyrosine phosphorylation upon challenge of theplatelet thrombin receptor, which requires the engagement of αIIbβ3integrin and PI3K activity (Laffargue, et al., FEBS Lett. 1999, 443(1),66-70). It has also been implicated in GPIbα-dependent thrombusstability at sites of vascular injury (Liu, et al., Blood 2006, 108(8),2596-603). Thus, BTK and Tec are involved in several processes importantin supporting the formation of a stable hemostatic plug, which iscritical for preventing significant blood loss in response to vascularinjury. Hence, the effects of the BTK inhibitor of Formula (XVIII) andibrutinib were evaluated on human platelet-mediated thrombosis byutilizing the in vivo human thrombus formation in the VWF HA1 mice modeldescribed in Chen et al. Nat. Biotechnol. 2008, 26(1), 114-19.

Administration of anesthesia, insertion of venous and arterialcatheters, fluorescent labeling and administration of human platelets(5×10⁸/ml), and surgical preparation of the cremaster muscle in micehave been previously described (Chen et al. Nat Biotechnol. 2008, 26(1),114-19). Injury to the vessel wall of arterioles (˜40-65 mm diameter)was performed using a pulsed nitrogen dye laser (440 nm, PhotonicInstruments) applied through a 20× water-immersion Olympus objective(LUMPlanF1, 0.5 numerical aperature (NA)) of a Zeiss Axiotech variomicroscope. Human platelet and wall interactions were visualized byfluorescence microscopy using a system equipped with a Yokogawa CSU-22spinning disk confocal scanner, iXON EM camera, and 488 nm and 561 nmlaser lines to detect BCECF-labeled and rhodamine-labeled platelets,respectively (Revolution XD, Andor Technology). The extent of thrombusformation was assessed for 2 min after injury and the area (μm²) ofcoverage determined (Image IQ, Andor Technology). For the Formula(XVIII), Formula (XXVII) (CC-292), and Formula (XX-A) (ibrutinib)inhibition studies, the BTK inhibitors were were added to purified humanplatelets for 30 min before administration.

The in vivo throbus effects of the BTK inhibitors, Formula (XVIII),Formula (XXVII) (CC-292), and Formula (XX-A) (ibrutinib), were evaluatedon human platelet-mediated thrombosis by utilizing the in vivo humanthrombus formation in the VWF HA1 mice model, which has been previouslydescribed (Chen et al. Nat Biotechnol. 2008, 26(1), 114-19). Purifiedhuman platelets were preincubated with various concentrations of the BTKinhibitors (0.1 μM, 0.5 μM, or 1 μM) or DMSO and then administered toVWF HA1 mice, followed by laser-induced thrombus formation. The BTKinhibitor-treated human platelets were fluorescently labeled and infusedcontinuously through a catheter inserted into the femoral artery. Theirbehavior in response to laser-induced vascular injury was monitored inreal time using two-channel confocal intravital microscopy (Furie andFurie, J. Clin. Invest. 2005, 115(12), 2255-62). Upon induction ofarteriole injury untreated platelets rapidly formed thrombi with anaverage thrombus size of 6,450±292 mm² (mean±s.e.m.), as shown in FIG.55 and FIG. 56. Similarly, Formula (XVIII) (1 μM) treated plateletsformed a slightly smaller but not significantly different thrombi withan average thrombus size of 5733±393 mm² (mean±s.e.m.). In contrast, adramatic reduction in thrombus size occurred in platelets pretreatedwith 1 μM of Formula XX-A (ibrutinib), 2600±246 mm² (mean±s.e.m.),resulting in a reduction in maximal thrombus size by approximately 61%compared with control (P>0.001) (FIGS. 55 and 57). Similar results wereobtained with platelets pretreated with 500 nM of Formula (XVIII) oribrutinib: thrombus size of 5946±283 mm², and 2710±325 mm² respectively.These initial results may provide some mechanic background andexplanation on the reported 44% bleeding related adverse event rates inthe Phase III RESONATE™ study comparing ibrutinib with ofatumumab. Theresults obtained for Formula XXVII (CC-292) were similar to that forFormula XX-A (ibrutinib), as shown in FIGS. 55, 56, and 57. The effectof the BTK inhibitor concentration is shown in FIG. 58. These resultsdemonstrate the surprising advantage of the BTK inhibitor of Formula(XVIII), which does not interfere with thrombus formation, while the BTKinhibitors of Formula XXVII (CC-292) and Formula XX-A (ibrutinib)interfere with thrombus formation.

The objective of this study was to evaluate in vivo thrombus formationin the presence of BTK inhibitors. In vivo testing of novel antiplateletagents requires informative biomarkers. By utilizing a genetic modifiedmouse von Willebrand factor (VWFR1326H) model that supports human butnot mouse platelet-mediated thrombosis, we evaluated the effects ofFormula (XVIII), Formula XXVII (CC-292), and Formula XX-A (ibrutinib) onthrombus formation. These results show that Formula (XVIII) had nosignificant effect on human platelet-mediated thrombus formation whileFormula XX-A (ibrutinib) was able to limit this process, resulting in areduction in maximal thrombus size by 61% compared with control. FormulaXXVII (CC-292) showed an effect similar to Formula XX-A (ibrutinib).These results, which show reduced thrombus formation for ibrutinib atphysiologically relevant concentrations, may provide some mechanisticbackground for the Grade ≧3 bleeding events (eg, subdural hematoma,gastrointestinal bleeding, hematuria and postprocedural hemorrhage) thathave been reported in <6% of patients treated with Formula XX-A(ibrutinib).

GPVI platelet aggregation was measured for Formula (XVIII) and FormulaXX-A (ibrutinib). Blood was obtained from untreated humans, andplatelets were purified from plasma-rich protein by centrifugation.Cells were resuspended to a final concentration of 350,000/μL in buffercontaining 145 mmol/L NaCl, 10 mmol/L HEPES, 0.5 mmol/L Na₂HPO₄, 5mmol/L KCl, 2 mmol/L MgCl₂, 1 mmol/L CaCl₂, and 0.1% glucose, at pH 7.4.Stock solutions of Convulxin (CVX) GPVI were prepared on the day ofexperimentation and added to platelet suspensions 5 minutes (37° C.,1200 rpm) before the induction of aggregation. Aggregation was assessedwith a Chronolog Lumi-Aggregometer (model 540 VS; Chronolog, Havertown,Pa.) and permitted to proceed for 6 minutes after the addition ofagonist. The results are reported as maximum percent change in lighttransmittance from baseline with platelet buffer used as a reference.The results are shown in FIG. 59.

In FIG. 60, the results of CVX-induced (250 ng/mL) human plateletaggregation results before and 15 min after administration of the BTKinhibitors to 6 healthy individuals are shown.

The results depicted in FIG. 59 and FIG. 60 indicate that the BTKinhibitor of Formula XX-A (ibrutinib) significantly inhibits GPVIplatelet aggregation, while the BTK inhibitor of Formula (XVIII) doesnot, further illustrating the surprising benefits of the lattercompound.

Example 7—Study of a BTK Inhibitor and a Combination of a BTK Inhibitorand a PI3K Inhibitor in Canine Lymphoma

Canine B cell lymphoma exists as a pathological entity that ischaracterized by large anaplastic, centroblastic or immunoblasticlymphocytes with high proliferative grade, significant peripherallymphadenopathy and an aggressive clinical course. While some dogsrespond initially to prednisone, most canine lymphomas progress quicklyand must be treated with combination therapies, includingcyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP), orother cytotoxic agents. In their histopathologic features, clinicalcourse, and high relapse rate after initial treatment, canine B celllymphomas resemble diffuse large B cell lymphoma (DLBCL) in humans.Thus, responses of canine B cell lymphomas to experimental treatmentsare considered to provide proof of concept for therapeutic candidates inDLBCL.

In this example, companion dogs with newly diagnosed orrelapsed/refractory LSA were enrolled on a veterinary clinical trial ofthe BTK inhibitor of Formula (XVIII) (“Arm 1”) or the BTK inhibitor ofFormula (XVIII) and the PI3K-δ inhibitor of Formula (IX) (“Arm 2”).Enrollment has completed for Arm 1 and is ongoing for Arm 2. Withapproximately ⅓ of Arm 2 subjects treated, the preliminary results showthat combined treatment with the BTK inhibitor of Formula (XVIII) andthe PI3K-δ inhibitor of Formula (IX) may have greater efficacy thantreatment with the BTK inhibitor of Formula (XVIII) alone in aggressivelymphoma.

Twenty-one dogs were treated in Arm 1 with the BTK inhibitor of Formula(XVIII) at dosages of 2.5 mg/kg once daily to 20 mg/kg twice daily.Intra-subject dose escalation was allowed. Six of the 11 dogs thatinitiated at 2.5 or 5 mg/kg once daily were escalated and completed thestudy with dosages of 10 mg/kg twice daily. Among all the dose cohorts,8 dogs had shrinkage of target lesions >20%; the best tumor responseswere between 45-49% reduction in the sum of target lesions in two dogs.Complete responses (“CR”, disappearance of all evidence of disease perevaluator judgment; and absence of new lesions) were not observed in Arm1.

In the combination phase of the study (Arm 2), 7 dogs have been treatedwith 10 mg/kg the BTK inhibitor of Formula (XVIII) and the PI3K-δinhibitor of Formula (IX) at 2.5 or 3.5 mg/kg, on a twice dailyschedule. To date, 4 dogs had shrinkage of target lesions >20%; and thebest tumor responses were between 58-65% reduction in the sum of targetlesions, with one sustained CR observed. Initial reductions in the sumof target lesions were observed to deepen during the course of therapyin 4 of the 7 dogs. A summary of the results is presented in Table 5.

TABLE 5 Summary of the results of the canine lymphoma study. Formula(XVIII) and Formula (XVIII) Response Metric Formula (IX)^(a) monotherapySum LD^(b) decreased by ≧20% 4/7 (57.1%) 8/21 (38.1%) Sum LD^(b)decreased by ≧30% 2/7 (28.6%) 6/21 (28.6%) (PR) CR by investigatorevaluation 1/7 (14.3%) 0/21 Median time on study 25 days 24 days (allsubjects) Median time to best response 21 days  7 days ^(a)Arm 2 isstill recruiting subjects ^(b)LD, longest diameter of up to 5 targetlesion

These preliminary data suggest that in companion dogs with naturallyoccurring B cell lymphomas, treatment with the combination of the BTKinhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula (IX)may provide increased biological activity (tumor shrinkage and stabledisease) and may possibly lead to deeper responses than treatment withthe BTK inhibitor of Formula (XVIII) alone. Although the available datarepresent only ⅓ of the planned Arm 2 population, the extended responsetime (median time to best response) and observation of a CR among thefew dogs treated to date may be evidence of synergy between Formula(XVIII) and Formula (IX) in this highly aggressive disease.

1. A method of treating a hyperproliferative disorder in a subject,comprising co-administering to a subject in need thereof atherapeutically effective amount of a phosphoinositide 3-kinase (PI3K)inhibitor, or of a pharmaceutically acceptable salt thereof, incombination with a Bruton's tyrosine kinase (BTK) inhibitor, or of apharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein the PI3K inhibitor is selected from the group consisting of aPI3K-γ inhibitor, a PI3K-δ inhibitor, and a PI3K-γ,δ inhibitor.
 3. Themethod of claim 2, wherein the PI3K inhibitor is a PI3K-γ,δ inhibitor.4. The method of any one of claim 1, wherein the hyperproliferativedisorder is leukemia, lymphoma, or a solid tumor cancer.
 5. The methodof any one of claim 1, wherein the solid tumor cancer is selected fromthe group consisting of breast, lung, colorectal, thyroid, bone sarcomaand stomach cancers.
 6. The method of any one of claim 1, wherein thecombination of the PI3K inhibitor with the BTK inhibitor is administeredby oral, intravenous, intramuscular, intraperitoneal, subcutaneous ortransdermal means.
 7. The method of any one of claim 1, wherein the PI3Kinhibitor and/or BTK inhibitor is in the form of a pharmaceuticallyacceptable salt.
 8. The method of any one of claim 1, wherein the PI3Kinhibitor is administered to the subject before administration of theBTK inhibitor.
 9. The method of any one of claim 1, wherein the PI3Kinhibitor is administered concurrently with the administration of theBTK inhibitor.
 10. The method of any one of claim 1, wherein the PI3Kinhibitor is administered to the subject after administration of the BTKinhibitor.
 11. The method of any one of claim 1, wherein the PI3Kinhibitor is:

or a pharmaceutically-acceptable salt thereof, wherein: X¹ is C(R⁹) orN; X² is C(R₁₀) or N; Y is N(R¹¹), O or S; Z is CR⁸ or N; n is 0, 1, 2or 3; R¹ is a direct-bonded or oxygen-linked saturated, partiallysaturated or unsaturated 5-, 6- or 7-membered monocyclic ring containing0, 1, 2, 3 or 4 atoms selected from N, O and S, but containing no morethan one O or S, wherein the available carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring issubstituted by 0 or 1 R² substituents, and the ring is additionallysubstituted by 0, 1, 2 or 3 substituents independently selected fromhalo, nitro, cyano, C₁₋₄alkyl, OC₁ _(_) ₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl; R² is selected from halo,C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a). —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), OS(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² is selected fromC₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle,—(C₁₋₃alkyl)heteroaryl, —(C₁₋₃alkyl)heterocycle,—O(C₁₋₃alkyl)heteroaryl, —O(C₁₋₃alkyl)heterocycle,—NR^(a)(C₁₋₃alkyl)heteroaryl, —NR^(a)(C₁₋₃alkyl)heterocycle,—(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyl and —NR^(a)(C₁₋₃alkyl)phenyl allof which are substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl; R³ is selectedfrom H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)R^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R², —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)NR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl; R⁴is, independently, in each instance, halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl orC₁₋₄haloalkyl; R⁵ is, independently, in each instance, H, halo,C₁₋₆alkyl, C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3substituents selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl,C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; orboth R⁵ groups together form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or3 substituents selected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl,C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; R⁶is selected from H, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a), and—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a); R⁷ is selected from H, halo, C₁₋₆alkyl,C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), and —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a); R⁸ isselected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), —NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl; R⁹ is selected from H, halo,C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a)C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a),—N(R^(a))C(O)NR^(a)R^(a)N(R^(a)C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the C₁₋₆ alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), and —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is asaturated, partially-saturated or unsaturated 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O andS, but containing no more than one O or S, wherein the available carbonatoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), S(═O)₂N(R^(a))C(═O)R^(a), S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a); R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano,nitro, CO₂R^(a), C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —S(═O)R^(b), S(═O)₂R^(b) orS(═O)₂NR^(a)R^(a); R¹¹ is H or C₁₋₄alkyl; R^(a) is independently, ateach instance, H or R^(b); and R^(b) is independently, at each instance,phenyl, benzyl or C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆ alkyl beingsubstituted by 0, 1, 2 or 3 substituents selected from halo, C₁₋₄alkyl,C₁₋₃ haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl, and—N(C₁₋₄alkyl)C₁₋₄alkyl.
 12. The method of claim 11, wherein the PI3Kinhibitor is:

or a pharmaceutically acceptable salt thereof.
 13. The method of any oneof claim 1, wherein the PI3K inhibitor is:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable salt thereof,wherein Cy is aryl or heteroaryl substituted by 0 or 1 occurrence of R³and 0, 1, 2, or 3 occurrence(s) of R⁵; W_(b) ⁵ is CR⁸, CHR⁸, or N; R⁸ ishydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy,amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl ornitro; B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl, each of which is substituted with 0,1, 2, 3, or 4 occurrence(s) of R²; each R² is independently alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl,acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro,phosphate, urea, or carbonate; X is —(CH(R⁹))_(z)—; Y is —N(R⁹)—C(═O)—,—C(═O)—N(R⁹)—, —C(═O)—N(R⁹)—(CHR⁹)—, —N(R⁹)—S(═O)—, —S(═O)—N(R⁹)—,—S(═O)₂—N(R⁹)—, —N(R⁹)—C(═O)—N(R⁹) or —N(R⁹)S(═O)₂—; z is an integer of1, 2, 3, or 4; R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl,sulfonyl, sulfoxide, sulfone, sulfonamido, halo, cyano, aryl,heteroaryl, hydroxyl, or nitro; each R⁵ is independently alkyl, alkenyl,alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy,sulfonamido, halo, cyano, hydroxyl, or nitro; each R⁹ is independentlyhydrogen, alkyl, cycloalkyl, heterocyclyl, or heteroalkyl; or twoadjacent occurrences of R⁹ together with the atoms to which they areattached form a 4- to 7-membered ring; W_(d) is heterocyclyl, aryl,cycloalkyl, or heteroaryl, each of which is substituted with one or moreR¹⁰, R¹¹, R¹² or R¹³, and R¹⁰, R¹¹, R¹² and R¹³ are each independentlyhydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy,heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate orNR′R″ wherein R′ and R″ are taken together with nitrogen to form acyclic moiety.
 14. The method of claim 13, wherein the PI3K inhibitoris:

or a pharmaceutically acceptable salt thereof, wherein B is:

wherein W_(c) is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, andq is an integer of 0, 1, 2, 3, or 4; X is a bond or —(CH(R⁹))_(z)—, andz is an integer of 1; Y is —N(R⁹)—; W_(d) is:

X₁, X₂ and X₃ are each independently C, CR¹³ or N; and X₄, X₅ and X₆ areeach independently N, NH, CR¹³, S or O; R¹ is hydrogen, alkyl, alkenyl,alkynyl, alkoxy, amido, alkoxycarbonyl, sulfonamido, halo, cyano, ornitro; R² is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxyor nitro; R³ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, alkoxy, amido, amino, alkoxycarbonyl sulfonamido,halo, cyano, hydroxy or nitro; and each instance of R⁹ is independentlyhydrogen, alkyl, or heterocycloalkyl.
 15. The method of claim 14,wherein the PI3K inhibitor is

or a pharmaceutically acceptable salt thereof.
 16. The method of claim14, wherein the PI3K inhibitor is

or a pharmaceutically acceptable salt thereof.
 17. The method of any oneof claim 1, wherein the BTK inhibitor is:

or a pharmaceutically acceptable salt thereof, wherein X is CH, N, O orS; Y is C(R₆), N, O or S; Z is CH, N or bond; A is CH or N; B₁ is N orC(R₇); B₂ is N or C(R₈); B₃ is N or C(R₉); B₄ is N or C(R₁₀); R₁ isR₁₁C(O), R₁₂S(O), R₁₃SO₂ or (1-6C)alkyl optionally substituted with R₁₄;R₂ is H, (1-3C)alkyl or (3-7C)cycloalkyl; R₃ is H, (1-6C)alkyl or(3-7C)cycloalkyl); or R₂ and R₃ form, together with the N and C atomthey are attached to, a (3-7C)heterocycloalkyl optionally substitutedwith one or more fluorine, hydroxyl, (1-3C)alkyl, (1-3C)alkoxy or oxo;R₄ is H or (1-3C)alkyl; R₅ is H, halogen, cyano, (1-4C)alkyl,(1-3C)alkoxy, (3-6C)cycloalkyl, any alkyl group of which is optionallysubstituted with one or more halogen; or R₅ is (6-10C)aryl or(2-6C)heterocycloalkyl; R₆ is H or (1-3C)alkyl; or R₅ and R₆ togethermay form a (3-7C)cycloalkenyl, or (2-6C)heterocycloalkenyl; eachoptionally substituted with (1-3C)alkyl, or one or more halogen; R₇ isH, halogen, CF₃, (1-3C)alkyl or (1-3C)alkoxy; R₈ is H, halogen, CF₃,(1-3C)alkyl or (1-3C)alkoxy; or R₇ and R₈ together with the carbon atomsthey are attached to, form (6-10C)aryl or (1-9C)heteroaryl; R₉ is H,halogen, (1-3C)alkyl or (1-3C)alkoxy; R₁₀ is H, halogen, (1-3C)alkyl or(1-3C)alkoxy; R₁₁ is independently selected from a group consisting of(1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl each alkyl, alkenyl oralkynyl optionally substituted with one or more groups selected fromhydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, [(1-4C)alkyl]amino,di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, (6-10C)aryl and(3-7C)heterocycloalkyl; or R₁₁ is (1-3C)alkyl-C(O)—S-(1-3C)alkyl; or R₁₁is (1-5C)heteroaryl optionally substituted with one or more groupsselected from halogen and cyano; R₁₂ and R₁₃ are independently selectedfrom a group consisting of (2-6C)alkenyl and (2-6C)alkynyl bothoptionally substituted with one or more groups selected from hydroxyl,(1-4C)alkyl, (3-7C)cycloalkyl, [(1-4C)alkyl]amino, di[(1-4C)alkyl]amino,(1-3C)alkoxy, (3-7C)cycloalkoxy, (6-10C)aryl and (3-7C)heterocycloalkyl;or (1-5C)heteroaryl optionally substituted with one or more groupsselected from halogen and cyano; and R14 is independently selected froma group consisting of halogen, cyano, (2-6C)alkenyl and (2-6C)alkynyl,wherein both (2-6C)alkenyl and (2-6C)alkynyl are optionally substitutedwith one or more groups selected from hydroxyl, (1-4C)alkyl,(3-7C)cycloalkyl, (1-4C)alkylamino, di[(1-4C)alkyl]amino, (1-3C)alkoxy,(3-7C)cycloalkoxy, (6-10C)aryl, (1-5C)heteroaryl and(3-7C)heterocycloalkyl.
 18. The method of any one of claim 1, whereinthe BTK inhibitor is:

or a pharmaceutically acceptable salt thereof, wherein L_(a) is CH₂, O,NH or S; Ar is a substituted or unsubstituted aryl, or a substituted orunsubstituted heteroaryl; Y is an optionally substituted group selectedfrom the group consisting of alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl; Z is C(═O), OC(═O), NRC(═O),C(═S), S(═O)_(x), OS(═O)_(x), NRS(═O)_(x), where x is 1 or 2; R₇ and R₈are each H; or R₇ and R₈ taken together form a bond; R₆ is H; and R is Hor C₁-C₆alkyl.
 19. The method of any one of claim 1, wherein the BTKinhibitor is:

or a pharmaceutically acceptable salt thereof, wherein L_(a) is CH₂, O,NH or S; Ar is a substituted or unsubstituted aryl, or a substituted orunsubstituted heteroaryl; Y is an optionally substituted group selectedfrom the group consisting of alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl; Z is C(═O), OC(═O), NRC(═O),C(═S), S(═O)_(x), OS(═O)_(x), NRS(═O)_(x), where x is 1 or 2; R₇ and R₈are each H; or R₇ and R₈ taken together form a bond; R₆ is H; and R is Hor C₁-C₆alkyl.
 20. The method of any one of claim 1, wherein the BTKinhibitor is:

or a pharmaceutically acceptable salt thereof, wherein L_(a) is CH₂, O,NH or S; Ar is a substituted or unsubstituted aryl, or a substituted orunsubstituted heteroaryl; Y is an optionally substituted group selectedfrom the group consisting of alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl; Z is C(═O), OC(═O), NRC(═O),C(═S), S(═O)_(x), OS(═O)_(x), NRS(═O)_(x), where x is 1 or 2; R₇ and R₈are each H; or R₇ and R₈ taken together form a bond; R₆ is H; and R is Hor C₁-C₆alkyl.
 21. The method of any one of claim 1, wherein the BTKinhibitor is:

or a pharmaceutically acceptable salt thereof, wherein L_(a) is CH₂, O,NH or S; Ar is a substituted or unsubstituted aryl, or a substituted orunsubstituted heteroaryl; Y is an optionally substituted group selectedfrom the group consisting of alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl; Z is C(═O), OC(═O), NRC(═O),C(═S), S(═O)_(x), OS(═O)_(x), NRS(═O)_(x), where x is 1 or 2; R₇ and R₈are each H; or R₇ and R₈ taken together form a bond; R₆ is H; and R is Hor C₁-C₆alkyl.
 22. The method of any one of claim 1, wherein the BTKinhibitor is:

or a pharmaceutically acceptable salt thereof, wherein: Q¹ is aryl,heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl, orheterocycloalkenyl, any of which is optionally substituted by one tofive independent G¹ substituents; R¹ is alkyl, cycloalkyl, bicycloalkyl,aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, orheterobicycloalkyl, any of which is optionally substituted by one ormore independent G¹¹ substituents; G¹ and G⁴¹ are each independentlyhalo, oxo, —CF₃, —OCF₃, —OR², —NR²R³(R^(3a))_(j1), —C(O)R², —CO₂R²,—CONR²R³, —NO₂, —CN, —S(O)_(j1)R², —SO₂NR²R³, NR²(C═O)R³, NR²(C═O)OR³,NR²(C═O)NR²R³, NR²S(O)_(j1)R³, —(C═S)OR², —(C═O)SR²,—NR²(C═NR³)NR^(2a)R^(3a), —NR²(C═NR³)OR^(2a), —NR²(C═NR³)SR^(3a),—O(C═O)OR², —O(C═O)NR²R³, —O(C═O)SR², —S(C═O)OR², —S(C═O)NR²R³,C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted withone or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²,—NR²²²R³³³(R³³³a)_(j1a), —C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —NO₂, —CN,—S(O)_(j1a)R²²², —SO₂NR²²²R³³³, NR²²²(C═O)R³³³, NR²²²(C═O)OR³³³,NR²²²(C═O)NR²²²R³³³, NR²²²S(O)_(j1a)R³³³, —(C═S)OR²²², —(C═O)SR²²²,NR²²²(C═NR³³³)NR^(222a)R^(333a), —NR²²²(C═NR³³³)OR^(222a),—NR²²²(C═NR³³³)SR^(333a), —O(C═O)OR²²², —O(C═O)NR²²²R³³³, —O(C═O)SR²²²,—S(C═O)OR²²², or —S(C═O)NR²²²R³³³ substituents; or—(X¹)_(n)—(Y¹)_(m)—R⁴; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, oraryl-C₂₋₁₀alkynyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³(R^(333a))_(j2a),—C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —NO₂, —CN, —S(O)_(j2a)R²²²,—SO₂NR²²²R³³³, NR²²²(C═O)R³³³, NR²²²(C═O)OR³³³, NR²²²(C═O)NR²²²R³³³,NR²²²S(O)_(j2a)R³³³, —(C═S)OR²²², —(C═O)SR²²²,NR²²²(C═NR³³³)NR^(222a)R^(333a), —NR²²²(C═NR³³³)OR^(222a),—NR²²²(C═NR³³³)SR^(333a), —O(C═O)OR²²², —O(C═O)NR²²²R³³³, —O(C═O)SR²²²,—S(C═O)OR²²², or —S(C═O)NR²²²R³³³ substituents; or hetaryl-C₀₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR²²², —NR²²², R³³³(R^(333a))_(j3a), —C(O)R²²², —CO₂R²²², —CONR²²²R³³³,—NO₂, —CN, —S(O)_(j3a)R²²², SO₂NR²²²R³³³, NR²²²(C═O)R³³³,NR²²²(C═O)OR³³³, NR²²²(C═O)NR²²²R³³³, NR²²²S(O)_(j3a)R³³³, —(C═S)OR²²²,—(C═O)SR²²², —NR²²²(C═NR³³³)NR²²²aR³³³a, —NR²²²(C═NR³³³)OR^(222a),—NR²²²(C═NR³³³)SR³³³a, —O(C═O)OR²²², —O(C═O)NR²²²R³³³, —O(C═O)SR²²²,—S(C═O)OR²²², or —S(C═O)NR²²²R³³³ substituents; G¹¹ is halo, oxo, —CF₃,—OCF₃, —OR²¹, —NR²¹R³¹(R^(3a1))_(j4), —C(O)R²¹, —CO₂R²¹, —CONR²¹R³¹,—NO₂, —CN, —S(O)_(j4)R²¹, —SO₂NR²¹R³¹, NR²¹(C═O)R³¹, NR²¹(C═O)OR³¹,NR²¹(C═O)NR²¹R³¹, RN²¹S(O)_(j4)R³¹, —(C═S)OR²¹, —(C═O)SR²¹, —NR²¹(C═NR³¹)NR^(2a1)R^(3a1), —NR²¹(C═NR³¹)OR^(2a1), —NR²¹(C═NR³¹)SR^(3a1),—O(C═O)OR²¹, —O(C═O)NR²¹R³¹, —O(C═O)SR²¹, —S(C═O)OR²¹, —S(C═O)NR²¹R³¹,—P(O)OR²¹OR³¹, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted withone or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(333a1))_(j4a), C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹, NR²²²¹(C═O)R³³³¹,NR²²²¹(C═O)OR³³³¹, NR²²²¹(C═O)NR²²²¹R³³³¹, NR²²²¹S(O)_(j4a)R³³³¹,—(C═S)OR²²²¹, —(C═O)SR²²²¹, NR²²²¹(C═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹(C═NR³³³¹)OR^(222a1), —NR²²²¹(C═NR³³³¹)SR^(333a1), —O(C═O)OR²²²¹,—O(C═O)NR²²²¹R³³³¹, —O(C═O)SR²²²¹, —S(C═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—S(C═O)NR²²²¹R³³³¹ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl,or aryl-C₂₋₁₀alkynyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR²²²¹,—NR²²²¹R³³³¹(R^(333a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, NR²²²¹(C═O)R³³³¹,NR²²²¹(C═O)OR³³³¹, NR²²²¹(C═O)NR²²²¹R³³³¹, NR²²²¹S(O)_(j5a)R³³³¹,—(C═S)OR²²²¹, —(C═O)SR²²²¹, —NR²²²¹(C═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹(C═NR³³³¹)OR^(222a1), —NR²²²¹(C═NR³³³¹)SR^(333a1), —O(C═O)OR²²²¹,—O(C═O)NR²²²¹R³³³¹, —O(C═O)SR²²²¹, —S(C═O)OR²²²¹, —P(O)OR²²²¹R³³³¹, or—S(C═O)NR²²²¹R³³³¹ substituents; or hetaryl-C₀₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR²²²¹, —NR²²²¹R³³³¹(R^(333a1))_(j6a), —C(O)R²²²¹, —CO₂R²²²¹,—CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j6a)R²²²¹, —SO₂NR²²²¹R³³³¹,NR²²²¹(C═O)R³³³¹, NR²²²¹(C═O)OR³³³¹, NR²²²¹(C═O)NR²²²¹R³³³¹,NR²²²¹S(O)_(j6a)R³³³¹, —(C═S)OR²²²¹, —(C═O)SR²²²¹,—NR²²²¹(C═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹(C═NR³³³¹)OR^(222a1),—NR²²²¹(C═NR³³³¹)SR^(333a1), —O(C═O)OR²²²¹, —O(C═O)NR²²²¹R³³³¹,—O(C═O)SR²²²¹, —S(C═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —S(C═O)NR²²²¹R³³³¹substituents; or G¹¹ is taken together with the carbon to which it isattached to form a double bond which is substituted with R⁵ and G¹¹¹;R², R^(2a), R³, R^(3a), R²²², R²²²a, R³³³, R^(333a), R²¹, R^(2a1), R³¹,R^(3a1), R²²²¹, R^(222a1), R³³³¹, and R^(333a1) are each independentlyequal to C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted by oneor more G¹¹¹ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, oraryl-C₂₋₁₀alkynyl, hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, orhetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted by one ormore G¹¹¹ substituents; or in the case of —NR²R³(R^(3a))_(j1) or—NR²²²R³³³(R³³³a)_(j1a) or —NR²²²R³³³(R³³³a)j2a or—NR²²²¹R³³³¹(R^(333a1))_(j3a) or —NR²²²¹R³³³¹(R^(333a1))_(j4a) or—NR²²²¹R³³³¹(R^(333a1))_(j5a) or —NR²²²¹R³³³¹(R^(333a1))_(j6a), R² andR³ or R²²² and R³³³3 or R²²²¹ and R³³³¹ taken together with the nitrogenatom to which they are attached form a 3-10 membered saturated ring,unsaturated ring, heterocyclic saturated ring, or heterocyclicunsaturated ring, wherein said ring is optionally substituted by one ormore G¹¹¹ substituents; X¹ and Y¹ are each independently —O—, —NR⁷—,—S(O)_(j7)—, —CR⁵R⁶—, —N(C(O)OR⁷)—, —N(C(O)R⁷)—, —N(SO₂R⁷)—, —CH₂O—,—CH₂S—, —CH₂N(R⁷)—, —CH(NR⁷)—, —CH₂N(C(O)R⁷)—, —CH₂N(C(O)OR⁷)—,—CH₂N(SO₂R⁷)—, —CH(NHR⁷)—, —CH(NHC(O)R⁷)—, —CH(NHSO₂R⁷)—,—CH(NHC(O)OR⁷)—, —CH(OC(O)R⁷)—, —CH(OC(O)NHR⁷)—, —CH═CH—, —C(═NOR⁷)—,—C(O)—, —CH(OR⁷)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂——OC(O)N(R⁷)—, —N(R⁷)C(O)N(R⁷)—, —NR⁷C(O)O—, —S(O)N(R⁷)—, —S(O)₂N(R⁷)—,—N(C(O)R⁷)S(O)—, —N(C(O)R⁷)S(O)₂—, —N(R⁷)S(O)N(R⁷)—, —N(R⁷)S(O)₂N(R⁷)—,—C(O)N(R⁷)C(O)—, —S(O)N(R⁷)C(O)—, —S(O)₂N(R⁷)C(O)—, —OS(O)N(R⁷)—,—OS(O)₂N(R⁷)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂O—, —N(R⁷)S(O)C(O)—,—N(R⁷)S(O)₂C(O)—, —SON(C(O)R⁷)—, —SO₂N(C(O)R⁷)—, —N(R⁷)SON(R⁷)—,—N(R⁷)SO₂N(R⁷)—, —C(O)O—, —N(R⁷)P(OR⁸)O—, —N(R⁷)P(OR⁸)—,—N(R⁷)P(O)(OR⁸)O—, —N(R⁷)P(O)(OR⁸)—, —N(C(O)R⁷)P(OR⁸)O—,—N(C(O)R⁷)P(OR⁸)—, —N(C(O)R⁷)P(O)(OR⁸)O—, —N(C(O)R⁷)P(OR⁸)—,—CH(R⁷)S(O)—, —CH(R⁷)S(O)₂—, —CH(R⁷)N(C(O)OR⁷)—, —CH(R⁷)N(C(O)R⁷)—,—CH(R⁷)N(SO₂R⁷)—, —CH(R⁷)O—, —CH(R⁷)S—, —CH(R⁷)N(R⁷)—,—CH(R⁷)N(C(O)R⁷)—, —CH(R⁷)N(C(O)OR⁷)—, —CH(R⁷)N(SO₂R⁷)—,—CH(R⁷)C(═NOR⁷)—, —CH(R⁷)C(O)—, —CH(R⁷)CH(OR⁷)—, —CH(R⁷)C(O)N(R⁷)—,—CH(R⁷)N(R⁷)C(O)—, —CH(R⁷)N(R⁷)S(O)—, —CH(R⁷)N(R⁷)S(O)₂—,—CH(R⁷)OC(O)N(R⁷)—, —CH(R⁷)N(R⁷)C(O)N(R⁷)—, —CH(R⁷)NR⁷C(O)O—,—CH(R⁷)S(O)N(R⁷)—, —CH(R⁷)S(O)₂N(R⁷)—, —CH(R⁷)N(C(O)R⁷)S(O)—,—CH(R⁷)N(C(O)R⁷)S(O)—, —CH(R⁷)N(R⁷)S(O)N(R⁷)—, —CH(R⁷)N(R⁷)S(O)₂N(R⁷)—,—CH(R⁷)C(O)N(R⁷)C(O)—, —CH(R⁷)S(O)N(R⁷)C(O)—, —CH(R⁷)S(O)₂N(R⁷)C(O)—,—CH(R⁷)OS(O)N(R⁷)—, —CH(R⁷)OS(O)₂N(R⁷)—, —CH(R⁷)N(R⁷)S(O)O—,—CH(R⁷)N(R⁷)S(O)₂O—, —CH(R⁷)N(R⁷)S(O)C(O)—, —CH(R⁷)N(R⁷)S(O)₂C(O)—,—CH(R⁷)SON(C(O)R⁷)—, —CH(R⁷)SO₂N(C(O)R⁷)—, —CH(R⁷)N(R⁷)SON(R⁷)—,—CH(R⁷)N(R⁷)SO₂N(R⁷)—, —CH(R⁷)C(O)O—, —CH(R⁷)N(R⁷)P(OR⁸)O—,—CH(R⁷)N(R⁷)P(OR⁸)—, —CH(R⁷)N(R⁷)P(O)(OR⁸)O—, —CH(R⁷)N(R⁷)P(O)(OR⁸)—,—CH(R⁷)N(C(O)R⁷)P(OR⁸)O—, —CH(R⁷)N(C(O)R⁷)P(OR⁸)—,—CH(R⁷)N(C(O)R⁷)P(O)(OR⁸)O—, or —CH(R⁷)N(C(O)R⁷)P(OR⁸)—; or X¹ and Y¹are each independently represented by one of the following structuralformulas:

R¹⁰, taken together with the phosphinamide or phosphonamide, is a 5-,6-, or 7-membered aryl, heteroaryl or heterocyclyl ring system; R⁵, R⁶,and G¹¹¹ are each independently a C₀₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl,C₁₋₁₀alkoxyC₂₋₁₀alkynyl, C₁₋₁₀alkylthioC₁₋₁₀alkyl,C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted withone or more independent halo, —CF₃, —OCF₃, —OR⁷⁷, —NR⁷⁷R⁸⁷, —C(O)R⁷⁷,—CO₂R⁷⁷, —CONR⁷⁷R⁸⁷, —NO₂, —CN, —S(O)_(j5a)R⁷⁷, —SO₂NR⁷⁷R⁸⁷,NR⁷⁷(C═O)R⁸⁷, NR⁷⁷(C═O)OR⁸⁷, NR⁷⁷(C═O)NR⁷⁸R⁸⁷, NR⁷⁷S(O)_(j5a)R⁸⁷,—(C═S)OR⁷⁷, —(C═O)SR⁷⁷, —NR⁷⁷(C═NR⁸⁷)NR⁷⁸R88, —NR⁷⁷(C═NR⁸⁷)OR⁷⁸,—NR⁷⁷(C═NR⁸⁷)SR⁷⁸, —O(C═O)OR⁷⁷, —O(C═O)NR⁷⁷R⁸⁷, —O(C═O)SR⁷⁷,—S(C═O)OR⁷⁷, —P(O)OR⁷⁷OR⁸⁷, or —S(C═O)NR⁷⁷R⁸⁷ substituents; oraryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of whichis optionally substituted with one or more independent halo, —CF₃,—OCF₃, —OR⁷⁷, —NR⁷⁷R⁸⁷, —C(O)R⁷⁷, —CO₂R⁷⁷, —CONR⁷⁷R⁸⁷, —NO₂, —CN,—S(O)_(j5a)R⁷⁷, —SO₂NR⁷⁷R⁸⁷, NR⁷⁷(C═O)R⁸⁷, NR⁷⁷(C═O)OR⁸⁷,NR⁷⁷(C═O)NR⁷⁸R⁸⁷, NR⁷⁷S(O)_(j5a)R⁸⁷, —(C═S)OR⁷⁷, —(C═O)SR⁷⁷,—NR⁷⁷(C═NR⁸⁷)NR⁷⁸R⁸⁸, —NR⁷⁷(C═NR⁸⁷)OR⁷⁸, —NR⁷⁷(C═NR⁸⁷)SR⁷⁸, —O(C═O)OR⁷⁷,—O(C═O)NR⁷⁷R⁸⁷, —O(C═O)SR⁷⁷, —S(C═O)OR⁷⁷, —P(O)OR⁷⁷R⁸⁷, or—S(C═O)NR⁷⁷R⁸⁷ substituents; or hetaryl-C₀₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR⁷⁷, —NR⁷⁷R⁸⁷, —C(O)R⁷⁷, —CO₂R⁷⁷, —CONR⁷⁷R⁸⁷, —NO₂, —CN,—S(O)_(j5a)R⁷⁷, —SO₂NR⁷⁷R⁸⁷, NR⁷⁷(C═O)R⁸⁷, NR⁷⁷(C═O)OR⁸⁷,NR⁷⁷(C═O)NR⁷⁸R⁸⁷, NR⁷⁷S(O)_(j5a)R⁸⁷, —(C═S)OR⁷⁷, —(C═O)SR⁷⁷,—NR⁷⁷(C═NR⁸⁷)NR⁷⁸R⁸⁸, —NR⁷⁷(C═NR⁸⁷)OR⁷⁸, —NR⁷⁷(C═NR⁸⁷)SR⁷⁸, —O(C═O)OR⁷⁷,—O(C═O)NR⁷⁷R⁸⁷, —O(C═O)SR⁷⁷, —S(C═O)OR⁷⁷, —P(O)OR⁷⁷OR⁸⁷, or—S(C═O)NR⁷⁷R⁸⁷ substituents; or R⁵ with R⁶ taken together with therespective carbon atom to which they are attached, form a 3-10 memberedsaturated or unsaturated ring, wherein said ring is optionallysubstituted with R⁶⁹; or R⁵ with R⁶ taken together with the respectivecarbon atom to which they are attached, form a 3-10 membered saturatedor unsaturated heterocyclic ring, wherein said ring is optionallysubstituted with R⁶⁹; R⁷ and R⁸ are each independently H, acyl, alkyl,alkenyl, aryl, heteroaryl, heterocyclyl or cycloalkyl, any of which isoptionally substituted by one or more G¹¹¹ substituents; R⁴ is H, alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,cycloalkenyl, or heterocycloalkenyl, any of which is optionallysubstituted by one or more G⁴¹ substituents; R⁶⁹ is equal to halo,—OR⁷⁸, —SH, —NR⁷⁸R⁸⁸, —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂, —CN, —S(O)_(j8)R⁷⁸,—SO₂NR⁷⁸R⁸⁸, C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxyC₁₋₁₀alkyl, C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, orheterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted withone or more independent halo, cyano, nitro, —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸, or—NR⁷⁷⁸R⁸⁸⁸ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, oraryl-C₂₋₁₀alkynyl, any of which is optionally substituted with one ormore independent halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸substituents; or hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, orhetaryl-C₂₋₁₀alkynyl, any of which is optionally substituted with one ormore independent halo, cyano, nitro, —OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,C₁₋₄alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which isoptionally substituted with one or more independent halo, cyano, nitro,—OR⁷⁷⁸, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,—CONR⁷⁷⁸R⁸⁸⁸ SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the case of—NR⁷⁸R⁸⁸, R⁷⁸ and R⁸⁸ taken together with the nitrogen atom to whichthey are attached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent halo,cyano, hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸substituents; R⁷⁷, R⁷⁸, R⁸⁷, R⁸⁸, R⁷⁷⁸, and R⁸⁸⁸ are each independentlyC₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxyC₁₋₁₀alkyl,C₁₋₁₀alkoxyC₂₋₁₀alkenyl, C₁₋₁₀alkoxyC₂₋₁₀alkynyl,C₁₋₁₀alkylthioC₁₋₁₀alkyl, C₁₋₁₀alkylthioC₂₋₁₀alkenyl,C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,cycloC₃₋₈alkylC₁₋₁₀alkyl, cycloC₃₋₈alkenylC₁₋₁₀alkyl,cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl,heterocyclyl-C₂₋₁₀alkynyl, C₁₋₁₀alkylcarbonyl, C₂₋₁₀alkenylcarbonyl,C₂₋₁₀alkynylcarbonyl, C₁₋₁₀alkoxycarbonyl,C₁₋₁₀alkoxycarbonylC₁₋₁₀alkyl, monoC₁₋₆alkylaminocarbonyl,diC₁₋₆alkylaminocarbonyl, mono(aryl)aminocarbonyl,di(aryl)aminocarbonyl, or C₁₋₁₀alkyl(aryl)aminocarbonyl, any of which isoptionally substituted with one or more independent halo, cyano,hydroxy, nitro, C₁₋₁₀alkoxy, —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), or—N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or aryl-C₀₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, or aryl-C₂₋₁₀alkynyl, any of which is optionallysubstituted with one or more independent halo, cyano, nitro,—O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,—CON(C₀₋₄alkyl)(C₀₋₁₀alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), or—N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or hetaryl-C₀₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, any of which isoptionally substituted with one or more independent halo, cyano, nitro,—O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,—CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), or—N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; or mono(C₁₋₆alkyl)aminoC₁₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono(aryl)aminoC₁₋₆alkyl,di(aryl)aminoC₁₋₆alkyl, or —N(C₁₋₆alkyl)-C₁₋₆alkyl-aryl, any of which isoptionally substituted with one or more independent halo, cyano, nitro,—O(C₀₋₄alkyl), C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, haloC₁₋₁₀alkyl,haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH, C₁₋₄alkoxycarbonyl,—CON(C₀₋₄alkyl)(C₀₋₄alkyl), —SO₂N(C₀₋₄alkyl)(C₀₋₄alkyl), or—N(C₀₋₄alkyl)(C₀₋₄alkyl) substituents; and n, m, j1, j1a, j2a, j3a, j4,j4a, j5a, j6a, j7, and j8 are each independently equal to 0, 1, or 2.23. The method of any one of claim 1, wherein the BTK inhibitor is:

or a pharmaceutically-acceptable salt thereof, and the PI3K inhibitoris:

or a pharmaceutically-acceptable salt thereof.
 24. The method of claim1, wherein the BTK inhibitor is(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamideor apharmaceutically-acceptable salt thereof, and the PI3K inhibitor orPI3K-δ inhibitor is(S)—N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amineor a pharmaceutically-acceptable salt thereof.
 25. The method of any oneof claim 1, which is a method of treating a cancer in a human comprisingadministering a therapeutically effective dose of a BTK inhibitor and aPI3K inhibitor in combination, wherein the dose is effective to inhibitsignaling between the cells of the cancer and at least onemicroenvironment selected from the group consisting of macrophages,monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory Tcells, natural killer cells, myeloid-derived suppressor cells,regulatory B cells, neutrophils, dendritic cells, and fibroblasts. 26.The method of claim 24, wherein the cancer is a solid tumor cancer. 27.The method of claim 25, wherein the solid tumor cancer is selected fromthe group consisting of colon carcinoma, pancreatic carcinoma, breastcancer, lung cancer, colorectal cancer, thyroid cancer, bone sarcoma,and stomach cancer.
 28. The method of any one of claim 24, wherein thedose is further effective to increase immune system recognition andrejection of the cancer by the human.
 29. (canceled)
 30. (canceled) 31.(canceled)
 32. A kit comprising a pharmaceutical composition comprisinga PI3K inhibitor and a pharmaceutical composition comprising a BTKinhibitor, for co-administration of the PI3K inhibitor and the BTKinhibitor, either simultaneously or separately.
 33. A method of treatinga cancer in a human sensitive to platelet-mediated thrombosis comprisingthe step of administering a therapeutically effective dose of a PI3Kinhibitor and a BTK inhibitor, wherein the BTK inhibitor is:

or a pharmaceutically-acceptable salt, cocrystal, hydrate, solvate, orprodrug thereof.
 34. The method of claim 32, wherein the PI3K inhibitoris:

or a pharmaceutically-acceptable salt, cocrystal, hydrate, solvate, orprodrug thereof.
 35. The method of any of claim 32, further comprisingthe step of administering a therapeutically effective dose of ananticoagulent or antiplatelet agent.
 36. The method of claim 34, whereinthe anticoagulent or antiplatelet agent is selected from the groupconsisting of clopidogrel, prasugrel, ticagrelor, ticlopidine, warfarin,acenocoumarol, dicumarol, phenprocoumon, heparain, low molecular weightheparin, fondaparinux, and idraparinux.
 37. The method of any of claim32, wherein the cancer is selected from the group consisting of bladdercancer, squamous cell carcinoma including head and neck cancer,pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, coloncarcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma,renal cell carcinoma, lung carcinoma, thyoma, prostate cancer,colorectal cancer, ovarian cancer, acute myeloid leukemia, thymuscancer, brain cancer, squamous cell cancer, skin cancer, eye cancer,retinoblastoma, melanoma, intraocular melanoma, oral cavity andoropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer,head, neck, renal cancer, kidney cancer, liver cancer, ovarian cancer,prostate cancer, colorectal cancer, esophageal cancer, testicularcancer, gynecological cancer, thyroid cancer, aquired immune deficiencysyndrome (AIDS)-related cancer, viral-induced cancer, glioblastoma,esophogeal tumors, hematological neoplasms, non-small-cell lung cancer,chronic myelocytic leukemia, diffuse large B-cell lymphoma, esophagustumor, follicle center lymphoma, head and neck tumor, hepatitis C virusinfection, hepatocellular carcinoma, Hodgkin's disease, metastatic coloncancer, multiple myeloma, non-Hodgkin's lymphoma, indolent non-Hogkin'slymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-celllung cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cellacute lymphoblastic leukemia (ALL), mature B-cell ALL, follicularlymphoma, mantle cell lymphoma, and Burkitt's lymphoma.
 38. A method oftreating a cancer in a human with a history of thrombosis, comprisingthe step of administering a therapeutically effective dose of a BTKinhibitor, wherein the BTK inhibitor is:

or a pharmaceutically-acceptable salt, cocrystal, hydrate, solvate, orprodrug thereof.